C-terminal hsp90 inhibitors

ABSTRACT

Hsp90 C-terminal inhibitors and pharmaceutical compositions containing such compounds are provided. The compounds of the disclosure are useful for the treatment and/or prevention of neurodegenerative disorders such as diabetic peripheral neuropathy.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/018,401, filed Jun. 26, 2018, which is a continuation of U.S.application Ser. No. 15/227,230, now U.S. Pat. No. 10,030,041, filedAug. 3, 2016, which is a continuation of U.S. application Ser. No.14/377,616, now U.S. Pat. No. 9,422,320, filed Aug. 8, 2014, as NationalStage Application of PCT/US2013/025387, filed Feb. 8, 2013, which claimsthe benefit of U.S. Provisional Ser. No. 61/597,004, filed Feb. 9, 2012.The foregoing applications are incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant Nos.CA120458, CA109265, NS054847 and DK073594, awarded by the NationalInstitutes of Health. The government has certain rights in theinvention.

FIELD OF THE INVENTION

The present invention is directed to novel C-terminal heat shock protein90 (Hsp 90) inhibitors with cytoprotective activity against sensoryneuron glucotoxicity.

DESCRIPTION OF RELATED ART

Approximately 26 million Americans are afflicted with either Type 1 orType 2 diabetes. Despite the use of insulin and oral anti-diabeticmedications to help maintain euglycemia, about 60-70% of theseindividuals develop diabetic peripheral neuropathy (DPN). Veves, A.;Backonja, M.; Malik, R. A., Painful diabetic neuropathy:Epidemiology,natural history, early diagnosis, and treatment options. Pain Med. 2008,9, 660-674.

To date, approaches toward the treatment of DPN have centered onpathways/targets directly limited to hyperglycemia (i.e., polyol &hexosamine pathways, advanced glycation end products (AGEs), enhancedoxidative stress, PKC activation). Tomlinson, D. R.; Gardiner, N. J.,Glucose neurotoxicity. Nat Rev Neurosci 2008, 9 (1), 36-45.

Unfortunately, the contribution of these targets/pathways to theprogression of DPN differs between individuals and does not occur withbiochemical uniformity, and consequently, these approaches have resultedin little success for the management of DPN. As an alternative approach,we have explored the pharmacologic modulation of molecular chaperones topromote a broad cytoprotective response that may enhance a patient'sability to tolerate hyperglycemic insults and improve the symptoms ofDPN.

Molecular chaperones, such as heat shock proteins 90 and 70 (Hsp90,Hsp70), are essential for folding nascent polypeptides into theirbiologically active structures and for the refolding of aggregated anddenatured proteins that occur upon cellular stress. Mayer, M. P.; Bukau,B., Hsp70 chaperones: cellular functions and molecular mechanism. CellMol Life Sci 2005, 62 (6), 670-84; Peterson, L. B.; Blagg, B. S., Tofold or not to fold: modulation and consequences of Hsp90 inhibition.Future Med Chem 2009, 1 (2), 267-283.

Numerous conditions that cause cell stress can also induce the “heatshock response” (HSR); the transcriptional upregulation of antioxidantgenes and chaperones such as Hsp70. Importantly, small moleculeinhibition of Hsp90 is sufficient to induce the HSR. KU-32 (FIG. 1) is asmall molecule Hsp90 C-terminal inhibitor that is based on novobiocin, anaturally occurring antimicrobial agent that inhibits DNA gyrase. KU-32is disclosed in U.S. Pat. No. 7,622,451 to Blagg et al. and U.S. Pat.No. 7,960,353 to Blagg. Although the etiology of DPN is unrelated to theaccumulation of one specific mis-folded or aggregated protein,hyperglycemia can increase oxidative stress and the oxidativemodification of amino acids (Obrosova, I. G., Diabetes and theperipheral nerve. Biochim Biophys Acta 2009, 10, 931-940; Akude, E.;Zherebitskaya, E.; Roy Chowdhury, S. K.; Girling, K.; Fernyhough, P.,4-Hydroxy-2-Nonenal Induces Mitochondrial Dysfunction and AberrantAxonal Outgrowth in Adult Sensory Neurons that Mimics Features ofDiabetic Neuropathy. Neurotox Res 2009, 1, 28-38) that impair proteinfolding, (Muchowski, P. J.; Wacker, J. L., Modulation ofneurodegeneration by molecular chaperones. Nat Rev Neurosci 2005, 6 (1),11-22) decrease mitochondrial protein import (Baseler, W. A.; Dabkowski,E. R.; Williamson, C. L.; Croston, T. L.; Thapa, D.; Powell, M. J.;Razunguzwa, T. T.; Hollander, J. M., Proteomic alterations of distinctmitochondrial subpopulations in the type 1 diabetic heart: contributionof protein import dysfunction. Am J Physiol Regul Integr Comp Physiol2011, 300 (2), R186-200) and promote mitochondrial dysfunction.Tomlinson et al., 2008 Id.; Obrosova et al., 2009 Id.

Even in the absence of a single, disease-specific protein aggregate, ithas been shown that pharmacologic induction of cytoprotective molecularchaperones can improve myelinated and unmyelinated fiber function incellular models of glucotoxic stress and animal models of DPN. Urban, M.J.; Li, C.; Yu, C.; Lu, Y.; Krise, J. M.; McIntosh, M. P.; Raj ewski, R.A.; Blagg, B. S. J.; Dobrowsky, R. T., Inhibiting Heat Shock Protein 90Reverses Sensory Hypoalgesia in Diabetic Mice. ASN Neuro 2010, 2, e00040DOI:189-199.

Mechanistically, KU-32 was ineffective at preventing neuregulin-induceddemyelination of myelinated cultures of sensory neurons prepared fromHsp70.1 and 70.3 double knockout mice, indicating that Hsp70 isnecessary for the neuroprotective activity manifested by KU-32.Similarly, weekly treatment with KU-32 restored normal sensory and motornerve function in diabetic wild type mice, but was unable to reversemultiple clinical indices of DPN in the diabetic Hsp70 knockout mice.Urban et al., 2010 Id. Collectively, these studies provide thebiological and clinical rationale to support the modulation of molecularchaperones as a viable approach toward the treatment of DPN.

An enviable aspect of KU-32 is that it induces Hsp70 at concentrationswell below those needed to inhibit Hsp90's protein folding ability.Urban et al., 2010 Id. Thus, KU-32 possesses a rather broad therapeuticwindow that dissociates cytoprotective properties from potentiallycytotoxic effects resulting from the degradation of Hsp90-dependentclient proteins. Peterson et al., 2009 Id. This lab previouslydemonstrated that molecules containing a benzamide, as found innovobiocin, exhibit anti-proliferative activities, whereas moleculescontaining an acetamide (e.g., KU-32) manifest neuroprotectiveproperties. However, these prior studies sought to evaluatestructureactivity relationships for novobiocin analogues as anti-canceragents, (Burlison, J. A.; Avila, C.; Vielhauer, G.; Lubbers, D. J.;Holzbeierlein, J.; Blagg, B. S., Development of novobiocin analoguesthat manifest anti-proliferative activity against several cancer celllines. J Org Chem 2008, 73 (6), 2130-7; Donnelly, A. C.; Mays, J. R.;Burlison, J. A.; Nelson, J. T.; Vielhauer, G.; Holzbeierlein, J.; Blagg,B. S. J., The Design, Synthesis, and Evaluation of Coumarin RingDerivatives of the Novobiocin Scaffold that Exhibit AntiproliferativeActivity. J Org. Chem. 2008, 73 (22), 8901-8920) rather than exploringchemical attributes that enhance the neuroprotective properties ofnovobiocin-based analogs. Therefore, diversification of the KU-32scaffold was explored to identify novel compounds which lack thecoumarin ring system yet surprisingly enhance the neuroprotectiveproperties manifested by Hsp90 C-terminal inhibitors.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to novel compounds useful as Hsp90inhibitors, and in particular as neuroprotective agents. In particular,the present invention is directed to the therapeutic use of suchcompounds in the treatment and/or prevention of diabetic peripheralneuropathy or other neurodegenerative disorders in a subject in needthereof.

In one embodiment, the disclosure provides a compound orpharmaceutically acceptable salt according to Formula (I):

wherein

R₁ is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl, alkynyl,carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino,alkoxy, halo, trifluoromethyl, sulfanyl, sulfenyl, sulfonyl, or ether;

R₂ is hydrogen, halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl,alkynyl, carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic,or —R₉—OR₁₀, wherein R₉ is a covalent bond or alkyl, and R₁₀ ishydrogen, alkyl, C-amido or acyl; or R₂ together with R₃ and the atomsto which they are attached form a carbocyclic ring with 5 to 7 ringmembers or a heterocyclic ring having 4 to 8 ring members with at leastone heteroatom selected from oxygen or nitrogen;

R₃ is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl,or —R₁₁-R₁₂, wherein R₁₁ is a covalent bond or alkyl, and R₁₂ is alkyl,C-amido or acyl; or R₃ together with R₂ and the atoms to which they areattached form a carbocyclic ring with 5 to 7 ring members or aheterocyclic ring having 4 to 8 ring members with at least oneheteroatom selected from oxygen or nitrogen;

R₄ is hydrogen, hydroxy, alkyl, arylalkoxy, carboxyl, —R₁₃—O—R₁₄, or—R₁₃-R₁₅; and wherein R¹³ is a covalent bond or alkyl, and R₁₄ ishydrogen, C-amido or acyl, and R₁₅ is N-amido, —POR₁₆R₁₇, —SO₂R₁₈, orsulfonamido, and wherein R₁₆, R₁₇, R₁₈ are independently alkoxy;

R₅ is hydrogen, hydroxy, alkyl, arylalkoxy, alkenyl, alkynyl, aryl, oraralkyl;

R₆ is hydrogen, hydroxy, sulfanyl, alkyl, alkenyl, alkynyl, aryl,arylalkyl, alkoxy, aryloxy, arylalkoxy or a heterocyclic ring having 4to 8 ring members with at least one heteroatom selected from oxygen ornitrogen;

R₇ is hydrogen, hydroxyl, arylalkoxy, alkyl, acyl, carboxyl or absent;

R₈ is hydrogen, hydroxyl, or arylalkoxy;

R₂₂ is hydrogen, hydroxy, amino, amido, cyano, alkoxy, halogen,trifluoroalkyl, alkyl, alkenyl, alkynyl, ester, nitro, carboxyl,aralkyl, aryl, carbocyclic, heterocyclic, trifluoromethyl, sulfonyl,sulfanyl, sulfenyl, ether, R₂₅—OR₂₆, or R₂₅—NR₂₆; where R₂₅ is acovalent bond or alkyl and R₂₆ is a hydrogen, alkyl, C-amido, or acyl;

R₂₃ is hydrogen, hydroxy, amino, amido, cyano, alkoxy, halogen,trifluoroalkyl, alkyl, alkenyl, alkynyl, ester, nitro, carboxyl,aralkyl, aryl, carbocyclic, heterocyclic, trifluoromethyl, sulfonyl,sulfanyl, sulfenyl, ether, R₂₇—OR₂₈, or R₂₇—NR₂₈; where R₂₇ is acovalent bond or alkyl and R₂₈ is a hydrogen, alkyl, C-amido, or acyl;or R₂₃ together with R₂₄ and the atoms to which they are attached form acarbocyclic ring with 5 to 7 ring members or a heterocyclic ring having4 to 8 members with at least one heteroatom selected from oxygen ornitrogen;

R₂₄ is hydrogen, hydroxy, amino, amido, cyano, alkoxy, halogen,trifluoroalkyl, alkyl, alkenyl, alkynyl, ester, nitro, carboxyl,aralkyl, aryl, carbocyclic, heterocyclic, trifluoromethyl, sulfonyl,sulfanyl, sulfenyl, ether, R₂₉—OR₃₀, or R₂₉—NR₃₀; where R₂₉ is acovalent bond or alkyl and R₃₀ is a hydrogen, alkyl, C-amido, or acyl;or R₂₄ together with R₂₃ and the atoms to which they are attached form acarbocyclic ring with 5 to 7 ring members or a heterocyclic ring having4 to 8 members with at least one heteroatom selected from oxygen ornitrogen;

X₁ is —CHR₁₉— or —CR₁₉═, and wherein R₁₉ is selected from hydrogen,halo, alkyl, alkenyl, or alkynyl; or X₁ together with X₂ form acarbocyclic ring having 3 to 7 ring members; or wherein X₁—X₂ is —C≡C—;

X₂ is —CHR₂₀— or ═CR₂₀—, and wherein R₂₀ is selected from hydrogen,halo, alkyl, alkenyl, or alkynyl; or X₂ together with X₁ form acarbocyclic ring having 3 to 7 ring members; or wherein X₁—X₂ is —C≡C—;

X₃ is O or CH₂;

X is ═CR₂₁— or ═N—, wherein R₂₁ is hydrogen, halo, trifluoromethyl,alkyl, alkenyl, alkynyl, alkoxy, or hydroxy;

R′ is H or alkyl;

R″ is alkyl, alkoxy, haloalkyl, alkylcycloalkyl or alkylamidoalkyl;

Y is ═CR₃— or ═N—;

Z is CH or Z—Z₁ is —C═C—;

Z₁ is CH, O, S, N, or Z—Z₁ is —C═C—; and

n is 0, 1, 2, or 3.

In some embodiments, the disclosure provides a compound or saltaccording to Formula (I) wherein X₁ is —CHR₁₉—, and R₁₉ is hydrogen oralkyl; or X₁ together with X₂ form a carbocyclic ring having 3 to 7 ringmembers; and X₂ is —CHR₂₀—, and wherein R₂₀ is hydrogen or alkyl; or X₂together with X₁ form a carbocyclic ring having 3 to 7 ring members.

In some embodiments, the disclosure provides a compound or saltaccording to Formula (I) wherein X₁ is CH₂ and X₂ is CH₂.

In some embodiments, the disclosure provides a compound or saltaccording to Formula (I) wherein R′ is H and R″ is CH₃.

In a further aspect, the disclosure provides a compound or saltaccording to Formula (I) wherein R₄ and R₅ are independently methyl orhydrogen.

In another aspect, the disclosure provides a compound or salt accordingto Formula (I) wherein R₆ is selected from hydrogen, hydroxy, methoxy,sulfanyl, or alkyl.

In another aspect, the disclosure provides a compound or salt accordingto Formula (I) wherein R₇ and R₈ are hydroxy.

In another aspect, the disclosure provides compounds of Formula (II):

wherein

R₁ is hydrogen, halo, hydroxy, trifluoroalkyl, alkoxy, or sulfanyl;

R₂ is hydrogen, halo, hydroxy, trifluoroalkyl, alkoxy, sulfanyl, oralkyl, or R₂ together with R₃ and the atoms to which they are attachedform a carbocyclic ring with 5 to 7 ring members or a heterocyclic ringhaving 4 to 8 ring members with at least one heteroatom selected fromoxygen or nitrogen;

R₃ is hydrogen, halo, hydroxy, trifluoroalkyl, alkoxy, sulfanyl, alkyl;or R₃ together with R₂ and the atoms to which they are attached form acarbocyclic ring with 5 to 7 ring members or a heterocyclic ring having4 to 8 ring members with at least one heteroatom selected from oxygen ornitrogen;

X is ═CR₂₁— or ═N—, wherein R₂₁ is hydrogen, halo, or trifluoromethyl;and

Y is ═CR₃— or ═N—.

In another aspect, the disclosure provides a compound or salt accordingto Formula (II) wherein R₁ is hydrogen, halo, alkoxy, or sulfanyl; R₂ ishydrogen, hydroxy, halo, trifluoroalkyl, alkoxy, or sulfanyl; R₃ ishydrogen, hydroxy, halo, trifluoroalkyl, alkoxy, or sulfanyl; X is═CR₂₁—, wherein R₂₁ is hydrogen, halo, or trifluoromethyl; and Y is═CR₃—.

In specific aspects, the disclosure provides compounds useful fortreating or preventing a neurodegenerative disorder selected fromN-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11a);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11b);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11c);N-(2-(2′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11d);N-(2-(3′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11e);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11f);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11g);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2′-(methylthio)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11h);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11i);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11j);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-methyl-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11k);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(morpholinomethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11l);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11m);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11m):N-(2-(benzo[d][1,3]dioxol-5-yl)-4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)phenethyl)acetamide(11n):N-(4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-(pyridin-3-yl)phenethyl)acetamide(11o);N-(4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-(pyridin-4-yl)phenethyl)acetamide(11p);N-(4′-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3″-fluoro-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide(20a);N-(4′-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3″-(trifluoromethyl)-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide(20b);N-(2-(5-((4-(benzyloxy)cyclohexyl)oxy)-3″-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(24);N-(2-(5-((4-(benzyloxy)cyclohex-2-en-1-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(36);N-(2-(5-((4-(benzyloxy)-2,3-dihydroxycyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(37);N-(2-(5-((4-(tert-butyl)cyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(39);N-(2-(3′-fluoro-5-((4-(piperidin-4-yl)cyclohexyl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(40);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-6-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(41);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-3-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(42); andN-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-4-methyl-[1,1′-biphenyl]-2-yl)ethyl)acetamide(43).

In a specific aspect, the compound is selected from:N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11b);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11c);N-(2-(2′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11d);N-(2-(3′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11e);N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11f); orN-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11g).

In another specific aspect, the compound is selected fromN-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11b);N-(2-(3′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11e); orN-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11f).

In some embodiments, the disclosure provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor pharmaceutically acceptable salt of a compound of Formula (I) whereinthe substituents are as defined above for R₁, R₂, R₃, R₄, R₅, R₆, R₇,R₈, R₂₂, R₂₃, R₂₄, Z, Z₁, X₁, X₂, X₃, R′, R″, X, Y and n in combinationwith a pharmaceutically acceptable carrier.

In some embodiments, the disclosure provides a compound of Formula (I)wherein X₃ is O. In some embodiments, the disclosure provides a compoundof Formula (I) wherein X₃ is CH₂. In some embodiments, the disclosureprovides a compound of Formula (I) wherein one of R₁, R₂ and R₃ is notH. In some embodiments, the disclosure provides a compound of Formula(I) wherein one of R₁, R₂ and R₃ is halo. In some embodiments, thedisclosure provides a compound of Formula (I) wherein one of R₂₂, R₂₃and R₂₄ is not H. In some embodiments, the disclosure provides acompound of Formula (I) wherein one of R₂₂, R₂₃ and R₂₄ is hydroxyl,alkoxy or alkyl. In some embodiments, the disclosure provides a compoundof Formula (I) wherein X₁ is —CH═, and X₂ is ═CH—. In some embodiments,the disclosure provides a compound of Formula (I) wherein X₁ and X₂ areboth CH₂. In some embodiments, the disclosure provides a compound ofFormula (I) wherein Z—Z₁ is —C═C—. In some embodiments, the disclosureprovides a compound of Formula (I) wherein R₄ and R₅ are independentlyalkyl. In some embodiments, the disclosure provides a compound ofFormula (I) wherein R₆ is alkoxy, aralkoxy or alkyl. In someembodiments, n=1.

In some embodiments, Z₁ is O and R₇ is absent. In some embodiments, Z₁is S and R₇ is absent. In some embodiments, Z₁ is N and R₇ is alkyl,hydrogen or carboxyl.

In some embodiments, the compound of Formula (I) is selected from acompound of Formula (Ia) wherein the substituents are as defined abovefor R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, X₁, X₂, R′, R″, X, Y and n.

In some embodiments, the compound of Formula (I) is selected from acompound of Formula (Ia) wherein the substituents are as defined abovefor R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, X₁, X₂, R′, R″, X, Y and n.

In other embodiments, the disclosure provides a method for treating orpreventing a neurodegenerative disorder in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of a compound or pharmaceutically acceptable salt of a compoundof Formula (I), wherein the substituents are defined above.

In other embodiments, the disclosure provides for use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a composition for treating a neurodegenerative disorderin a subject in need thereof; wherein the composition is to beadministered in an amount effective to alleviate or prevent symptoms ofneuronal glucotoxicity. In a specific embodiment, the neuronalglucotoxicity is sensory neuron glucotoxicity.

In another specific embodiment, the neurodegenerative disorder isdiabetic peripheral neuropathy.

In still another embodiment, the compounds of the present inventionexhibit neuroprotective effects by upregulation of Hsp70.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows chemical structures of novobiocin and KU-32.

FIGS. 2A-D. FIG. 2A shows a molecular model of KU-32 docked to Hsp90C-terminal binding site. FIG. 2B shows a molecular model of a novologue(structure shown in FIG. 2D) docked to Hsp90 C-terminal binding site.FIG. 2C shows an overlay of KU-32 and a novologue (structure shown inFIG. 2D) docked to Hsp90 C-terminal binding site. FIG. 2D shows thechemical structure of a novologue and its attributes.

FIG. 3 shows the determination of EC₅₀ of select novologues KU-32, 11f,11l, 11b, 11n, 11h, and 11o. DRG sensory neurons were incubated in theabsence or presence of 0.1-1000 nM of the indicated novologue overnightand then subjected to 4 hrs of hyperglycemia. Cell viability wasmeasured as described in Example 2 and the data expressed as percent ofnormoglycemic controls. Under hyperglycemic conditions and in theabsence of any novologues, cell viability was 20%±7.

FIG. 4 shows determination of EC₅₀ of select novologues KU-32, 11f, 11l,11b, 11n, 11h, and 11o from FIG. 3. The EC₅₀ was determined using theEC_(anything) function of GraphPad Prism 5.0 and the mean±SEM (n=3-8) isshown. #, p<0.05 versus KU-32.

FIG. 5 shows immunoblot analysis of induction of Hsp70 by selectnovologues KU-32, 11n and 11b. DRG sensory neurons were incubated in thepresence of DMSO (Cntrl) or 10-1000 nM of the indicated novologueovernight and then subjected to 4 hrs of hyperglycemia. The neurons wereharvested and Hsp70 and 3-actin levels were determined by immunoblotanalysis. Band intensity was quantified using Image J, Hsp70 expressionwas normalized to the level of β-actin.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

Molecular terms, when used in this application, have their commonmeaning unless otherwise specified. It should be noted that thealphabetical letters used in the formulas of the present inventionshould be interpreted as the functional groups, moieties, orsubstituents as defined herein. Unless otherwise defined, the symbolswill have their ordinary and customary meaning to those skilled in theart.

The term “acyl” refers to —COR wherein R used in this definition ishydrogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocylic, aryl, oraralkyl. Most preferably, R is hydrogen, alkyl, aryl, or aralkyl.

The term “amido” indicates either a C-amido group such as —CONR′R″ or anN-amido group such as —NR′COR″ wherein R′ and R″ as used in thisdefinition are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,carbocyclic, heterocylic, aryl, or aralkyl. A “sulfoamido” groupincludes the —NR′—SO₂—R″. Most preferably, R′ and R″ are hydrogen,alkyl, aryl, or aralkyl.

The term “amino” signifies a primary, secondary or tertiary amino groupof the formula —NR′R″ wherein R′ and R″ as used in this definition areindependently hydrogen, alkyl, alkyenyl, alkynyl, aralkyl, carbocyclic,heterocyclic, aralkyl, or other amino (in the case of hydrazide) or R′and R″ together with the nitrogen atom to which they are attached, forma ring having 4 to 8 atoms. Thus, the term “amino,” as used herein,includes unsubstituted, monosubstituted (e.g., monoalkylamino ormonoarylamino), and disubstituted (e.g., dialkylamino or aralkylamino)amino groups. Amino groups include —NH₂, methylamino, ethylamino,dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl, orpiperidino, morpholino, etc. Other exemplary “amino” groups forming aring include pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,indolyl, indazolyl, purinyl, quinolizinyl. The ring containing the aminogroup may be optionally substituted with another amino, alkyl, alkenyl,alkynyl, halo, or hydroxyl group.

The term “alkyl” refers to a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl,tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Preferred“alkyl” groups herein contain 1 to 12 carbon atoms. Most preferred are“lower alkyl” which refer to an alkyl group of one to six, morepreferably one to four, carbon atoms. The alkyl group may be optionallysubstituted with an amino, alkyl, cycloalkyl, halo, or hydroxyl group.

The term “alkoxy” denotes oxy-containing groups substituted with analkyl, or cycloalkyl group. Examples include, without limitation,methoxy, ethoxy, tert-butoxy, and cyclohexyloxy. Most preferred are“lower alkoxy” groups having one to six carbon atoms. Examples of suchgroups include methoxy, ethoxy, propoxy, butoxy, isopropoxy, andtert-butoxy groups.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double bond or triple bondrespectively.

The term “aryl” means a carbocyclic aromatic system containing one, two,or three rings wherein such rings may be attached together in a pendantmanner or may be fused. The term “fused” means that a second ring ispresent (i.e., attached or formed) by having two adjacent atoms incommon (i.e., shared) with the first ring. The term “fused” isequivalent to the term “condensed.” The term “aryl” embraces aromaticgroups such as phenyl, naphthyl, tetrahydronaphthyl, indane, andbiphenyl. The aryl group may optionally be substituted with an amino,alkyl, halo, hydroxyl, carbocyclic, heterocyclic, or another aryl group.

The term “aralkyl” embraces aryl-substituted alkyl moieties. Preferablearalkyl groups are “lower aralkyl” groups having aryl groups attached toalkyl groups having one to six carbon atoms. Examples of such groupsinclude benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, anddiphenylethyl. The terms benzyl and phenylmethyl are interchangeable.

The term “aryloxy” embraces aryl groups, as defined above, attached toan oxygen atom. The aryloxy groups may optionally be substituted with ahalo, hydroxyl, or alkyl group. Examples of such groups include phenoxy,4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy,3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4-fluorophenoxy,3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3-fluorophenoxy,4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthyloxy,3-isopropylphenoxy, 3-cyclopropylphenoxy, 3-ethylphenoxy,4-tert-butylphenoxy, 3-pentafluoroethylphenoxy, and3-(1,1,2,2-tetrafluoroethoxy)phenoxy.

The term “arylalkoxy” embraces oxy-containing aralkyl groups attachedthrough an oxygen atom to other groups. “Lower arylalkoxy” groups arethose phenyl groups attached to lower alkoxy group as described above.Examples of such groups include benzyloxy, 1-phenylethoxy,3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy,3,5-difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy,2-fluoro-3-trifluoromethylbenzyloxy, and 2-phenylethoxy.

The term “carboxyl” refers to —R′C(═O)OR″, wherein R′ and R″ as used inthis definition are independently hydrogen, alkyl, alkenyl, alkynyl,carbocyclic, heterocylic, aryl, or aralkyl or R′ can additionally be acovalent bond. “Carboxyl” includes both carboxylic acids, and carboxylicacid esters. The term “carboxylic acid” refers to a carboxyl group inwhich R″ is hydrogen. Such acids include formic, acetic, propionic,butyric, valeric acid, 2-methyl propionic acid, oxirane-carboxylic acid,and cyclopropane carboxylic acid. The term “carboxylic acid ester” or“ester” refers to a carboxyl group in which R″ is alkyl, alkenyl,alkynyl, carbocyclic, heterocylic, aryl, or aralkyl.

The term “carbocyclic” refers to a group that contains one or morecovalently closed ring structures, and that the atoms forming thebackbone of the ring are all carbon atoms. The ring structure may besaturated or unsaturated. The term thus distinguishes carbocyclic fromheterocyclic rings in which the ring backbone contains at least onenon-carbon atom. The term carbocylic encompasses cycloalkyl ringsystems.

The terms “cycloalkane” or “cyclic alkane” or “cycloalkyl” refer to acarbocyclic group in which the ring is a cyclic aliphatic hydrocarbon,for example, a cyclic alkyl group preferably with 3 to 12 ring carbons.“Cycloalkyl” includes, by way of example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like. Thecycloalkyl group may be optionally substituted with an amino, alkyl,halo, or hydroxyl group.

The term “ether” refers to the group —R′—O—R″ wherein R′ and R″ as usedin this definition are independently hydrogen, alkyl, alkenyl, alkynyl,carbocyclic, heterocylic, aryl, or aralkyl, and R′ can additionally be acovalent bond attached to a carbon.

The terms “halo” or “halogen” refer to fluoro, chloro, bromo, or iodo,usually regarding halo substitution for a hydrogen atom in an organiccompound.

The term “heterocyclic”, “het”, or “heterocycle” means an optionallysubstituted, saturated or unsaturated, aromatic or non-aromatic cyclichydrocarbon group with 4 to about 12 carbon atoms, preferably about 5 toabout 6, wherein 1 to about 4 carbon atoms are replaced by nitrogen,oxygen or sulfur. Exemplary heterocyclic which are aromatic includegroups piperidinyl, pyridinyl, furanyl, benzofuranyl, isobenzofuranyl,pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, indolyl,imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl,and tetrazolyl. Exemplary heterocycles include benzimidazole,dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine,dithiazole, dithiolane, furan, indole, 3-H indazole, 3-H-indole,imidazole, indolizine, isoindole, isothiazole, isoxazole, morpholine,oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine,piperazine, piperidine, purine, pyran, pyrazine, pyrazole, pyridine,pyrimidine, pyrimidine, pyridazine, pyrrole, pyrrolidine,tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole,thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine, andtriazole. The heterocycle may be optionally substituted with an amino,alkyl, alkenyl, alkynyl, halo, hydroxyl, carbocyclic, thio, otherheterocyclic, or aryl group. Exemplary heterocyclic groups include1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-pyridyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-imidazolyl, 2-imidazolyl,3-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 2 pyrazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 1-pyrazinyl, 2-pyrazinyl, 1-pyrimidinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 1-pyridazinyl,2-pyridazinyl, 3-pyridazinyl, 4-pyridizinyl, 1-indolizinyl,2-indolizinyl, 3-indolizinyl, 4-indolizinyl, 5-indolizinyl,6-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-isoindolyl, 2-isoindolyl,3-isoindolyl, 4-isoindolyl, 5-isoindolyl.

The term “hydroxy” or “hydroxyl” refers to the substituent —OH.

The term “oxo” shall refer to the substituent ═O.

The term “nitro” means —NO₂.

The term “sulfanyl” refers to —SR′ where R′ as used in this definitionis hydrogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocylic, aryl, oraralkyl.

The term “sulfenyl” refers to —SOR′ where R′ as used is this definitionis hydrogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocylic, aryl, oraralkyl.

The term “sulfonyl” refers to —SOR′ where R′ as used in this definitionis hydrogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocylic, aryl, oraralkyl.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. “Optionally” is inclusive of embodiments in which thedescribed conditions is present and embodiments in which the describedcondition is not present. For example, “optionally substituted phenyl”means that the phenyl may or may not be substituted, and that thedescription includes both unsubstituted phenyl and phenyl wherein thereis substitution. “Optionally” is inclusive of embodiments in which thedescribed conditions is present and embodiments in which the describedcondition is not present.

The compounds of the present invention can exist in tautomeric,geometric, or stereoisomeric forms. The present invention contemplatesall such compounds, including cis- and trans-geometric isomers, E- andZ-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers,l-isomers, the racemic mixtures thereof and other mixtures thereof, asfalling within the scope of the invention.

Also included in the family of compounds of the present invention arethe pharmaceutically acceptable salts, esters, and prodrugs thereof. Theterm “pharmaceutically-acceptable salts” embraces salts commonly used toform alkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically acceptable. Suitable pharmaceutically acceptable acidaddition salts of compounds of the present invention be prepared frominorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric,and phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic,cyclohexylaminosulfonic, algenic, galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of thepresent invention include metallic salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc or organic salts madefrom N,N′-dibenzylethyleneldiamine, choline, chloroprocaine,diethanolamine, ethylenediamine, meglumine (N-methylglucamine) andprocain. All of these salts may be prepared by conventional means fromthe corresponding compounds of by reacting, for example, the appropriateacid or base with the compounds of the present invention.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include, but are not limited to,those that break down readily in the human body to leave the parentcompound or a salt thereof. Suitable ester groups include, for example,those derived from pharmaceutically acceptable aliphatic carboxylicacids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioicacids, in which each alkyl or alkenyl moiety advantageously has not morethan 6 carbon atoms. Examples of particular esters include formates,acetates, propionates, butyrates, acrylates, and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, commensurate with areasonable risk/benefit ratio, and effective for their intended use,where possible, of the compounds of the invention. The term “prodrug”refers to compounds that are rapidly transformed in vivo to yield theparent compound of the above formulae, for example, by hydrolysis inblood. A thorough discussion is provided in T. Higuchi and V. Stella,Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. SymposiumSeries and in Edward B. Roche, ed., Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, (1987),both of which are incorporated by reference herein.

The term “neuroprotection” embraces inhibition of progressivedeterioration of neurons that leads to cell death.

The term “neurodegenerative disorder” embraces a disorder in whichprogressive loss of neurons occurs either in the peripheral nervoussystem or in the central nervous system. In one embodiment, thecondition treated and/or prevented by the compounds, compositions andmethods of the disclosure is a neurodegenerative disorder. Without beingbound by theory, it is believed that the compounds and compositions ofthe present disclosure provide neuroprotective effects of the Hsp90inhibitor(s) during the treatment of the neurodegenerative disorder byinhibiting the progressive deterioration of neurons that leads to celldeath.

In one aspect, the neurodegenerative disorder is sensory neuronglucotoxicity resultant from, e.g., hyperglycemia associated with adiabetic condition, and resultant in, e.g., diabetic peripheralneuropathy.

Examples of neurodegenerative disorders include, but are not limited tochronic neurodegenerative diseases such as diabetic peripheralneuropathy (including third nerve palsy, mononeuropathy, mononeuropathymultiplex, diabetic amyotrophy, autonomic neuropathy andthoracoabdominal neuropathy), Alzheimer's disease, age-related memoryloss, senility, age-related dementia, Pick's disease, diffuse Lewy bodydisease, progressive supranuclear palsy (Steel-Richardson syndrome),multisystem degeneration (Shy-Drager syndrome), motor neuron diseasesincluding amyotrophic lateral sclerosis (“ALS”), degenerative ataxias,cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam,subacute sclerosing panencephalitis, Huntington's disease, Parkinson'sdisease, multiple sclerosis (“MS”), synucleinopathies, primaryprogressive aphasia, striatonigral degeneration, Machado-Josephdisease/spinocerebellar ataxia type 3 and olivopontocerebellardegenerations, Gilles De La Tourette's disease, bulbar and pseudobulbarpalsy, spinal and spinobulbar muscular atrophy (Kennedy's disease),primary lateral sclerosis, familial spastic paraplegia,Wernicke-Korsakoffs related dementia (alcohol induced dementia),Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach'sdisease, Sandhoff disease, familial spastic disease,Wohifart-Kugelberg-Welander disease, spastic paraparesis, progressivemultifocal leukoencephalopathy, and prion diseases (includingCreutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru andfatal familial insomnia). Other conditions also included within themethods of the present invention include age-related dementia and otherdementias, and conditions with memory loss including vascular dementia,diffuse white matter disease (Binswanger's disease), dementia ofendocrine or metabolic origin, dementia of head trauma and diffuse braindamage, dementia pugilistica, and frontal lobe dementia. Also otherneurodegenerative disorders resulting from cerebral ischemia orinfarction including embolic occlusion and thrombotic occlusion as wellas intracranial hemorrhage of any type (including, but not limited to,epidural, subdural, subarachnoid, and intracerebral), and intracranialand intravertebral lesions (including, but not limited to, contusion,penetration, shear, compression, and laceration). Thus, the term alsoencompasses acute neurodegenerative disorders such as those involvingstroke, traumatic brain injury, schizophrenia, peripheral nerve damage,hypoglycemia, spinal cord injury, epilepsy, and anoxia and hypoxia.

In some embodiments, the neurodegenerative disorder is amyloidosis.Amyloidosis is observed in Alzheimer's Disease, hereditary cerebralangiopathy, nonneuropathic hereditary amyloid, Down's syndrome,macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wellssyndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis,chronic hemodialysis arthropathy, and Finnish and Iowa amyloidosis. Inpreferred embodiments, the neurodegenerative disorder treated and/orprevented using the methods and compositions of the disclosure isdiabetic peripheral neuropathy.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the analogue orderivative from one organ, or portion of the body, to another organ, orportion of the body. Each carrier must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which may serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The “patient” or “subject” to be treated with the compounds of thepresent invention can be any animal, e.g., dogs, cats, mice, monkeys,rats, rabbits, horses, cows, guinea pigs, sheep, and is preferably amammal, such as a domesticated animal or a livestock animal. In anotheraspect, the patient is a human.

The term “inhibit” or “inhibiting” refers to a statistically significantand measurable reduction in neurotoxicity, preferably as measured by oneor more of the assays discussed herein, preferably a reduction of atleast about 10% versus control, more preferably a reduction of about 50%or more, still more preferably a reduction of about 60%, 70%, 80%, 90%,or more.

The term “preventing” as used herein means that the compounds of thepresent invention are useful when administered to a patient who has notbeen diagnosed as possibly having the disorder or disease at the time ofadministration, but who would normally be expected to develop thedisorder or disease or be at increased risk for the disorder or disease.The compounds of the invention will slow the development of the disorderor disease symptoms, delay the onset of the disorder or disease, orprevent the individual from developing the disorder or disease at all.Preventing also includes administration of the compounds of theinvention to those individuals thought to be predisposed to the disorderor disease due to age, familial history, genetic or chromosomalabnormalities, and/or due to the presence of one or more biologicalmarkers for the disorder or disease.

The term “treating,” as used herein generally means that the compoundsof the invention can be used in humans or animals with at least atentative diagnosis of the disorder or disease. The compounds of theinvention will delay or slow the progression of the disorder or diseasethereby giving the individual a more useful life span. The term“treatment” embraces at least an amelioration of the symptoms associatedwith the disorder or disease in the patient is achieved, whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude of a parameter, e.g. symptom, associated with thecondition being treated. As such, “treatment” also includes situationswhere the diseased condition or disorder, or at least symptomsassociated therewith, are completely inhibited, e.g. prevented fromhappening, or stopped, e.g. terminated, such that the patient no longersuffers from the condition or disorder, or at least the symptoms thatcharacterize the condition or disorder.

A “therapeutically effective amount” is an amount of a compound of thepresent invention or a combination of two or more such compounds, whichinhibits, totally or partially, the progression of the condition oralleviates, at least partially, one or more symptoms of the condition. Atherapeutically effective amount can also be an amount that isprophylactically effective. The amount that is therapeutically effectivewill depend upon the patient's size and gender, the condition to betreated, the severity of the condition and the result sought. For agiven patient and condition, a therapeutically effective amount can bedetermined by methods known to those of skill in the art.

KU-32 is a first-generation novologue (a novobiocin-based, C-terminal,heat shock protein 90 (Hsp90) inhibitor) that decreases glucose-induceddeath of primary sensory neurons and reverses numerous clinical indicesof diabetic peripheral neuropathy in mice. The structures of KU-32 andNovobiocin are shown in FIG. 1. The disclosure provides a new series ofC-terminal Hsp90 inhibitors designed to optimize hydrogen bonding andhydrophobic interactions in an attempt to enhance neuroprotectiveactivity. A series of substituted phenylboronic acids was used in asynthetic route to replace the coumarin lactone of KU-32 with an arylmoiety, such as a biphenyl moiety. Electronegative atoms placed at themeta-position of the B-ring were identified that exhibit improvedcytoprotective activity, which while not wishing to be bound by theory,is believed to result from favorable interactions with Lys539 in theHsp90 C-terminal binding pocket. Consistent with these results, ameta-3-fluorophenyl substituted novologue (11b) surprisingly exhibited a14-fold lower ED₅₀ compared to KU-32 for protection againstglucose-induced toxicity of primary sensory neurons.

Recently, molecular modeling studies were performed by this lab andazide-containing novobiocin derivatives as photoaffinity probes wereused to elucidate, for the first time, the Hsp90 C-terminal bindingsite. Matts, R. L.; Dixit, A.; Peterson, L. B.; Sun, L.; Voruganti, S.;Kalyanaraman, P.; Hartson, S. D.; Verkhivker, G. M.; Blagg, B. S.,Elucidation of the Hsp90 C-Terminal Inhibitor Binding Site. ACS ChemBiol 2011. As shown in FIG. 2 (A-C), KU-32 docks to this region andappears to exhibit binding interactions with both the protein backboneand the amino acid side chains similar to those manifested bynovobiocin. Interestingly, the coumarin lactone of KU-32 appears toodistant from Lys539 to provide complementary interactions with thisresidue. In addition, the 3-amido side chain appears to project into alarge hydrophobic pocket that could accommodate more flexible linkers.As a consequence of these observations, the novologue scaffold (FIG. 2D)was designed to project the B-ring into the pocket where Lys539 residesand to serve as a lead compound for further diversification. Withoutbeing bound to theory, it is possible that the flexible ethyl amideprojecting from the A-ring could accommodate a number of orientationsthat could better occupy the large hydrophobic pocket that remainsvacant in the presence of KU-32.

Based on the novologue design, construction of a parallel library wasdesigned to validate this scaffold for use as a neuroprotective agent.The library was designed so that the 3′-carbamate on noviose wasomitted; based upon prior studies that showed this group to bedetrimental to Hsp90 inhibitory activity. Burlison, J. A.; Neckers, L.;Smith, A. B.; Maxwell, A.; Blagg, B. S. J., Novobiocin: Redesigning aDNA Gyrase Inhibitor for Selective Inhibition of Hsp90. Journal of theAmerican Chemical Society 2006, 128 (48), 15529-15536.

In contrast, additional hydrophobic and hydrogen bonding interactionsare provided by the incorporation of functionalities onto the 3-arylsubstituent (B-ring), which was designed to provide complementaryinteractions with Lys539. The 4-ethyl acetamide is included to occupythe binding pocket about the coumarin ring system. In one aspect,consistent with data obtained from prior studies, the 7-noviosyl linkageis maintained as well the requisite 2′,3′-diol. The disclosure providesthe parallel synthesis of rationally designed novologues as Hsp90C-terminal inhibitors and assessment of their neuroprotectiveactivities.

Retrosynthetically, a library of novologues was designed forconstruction via four components (Scheme 1); a resorcinolic benzaldehyde(1), a variety of commercially available boronic acids (2a-p), noviose(3), and the acetamide side chain (Scheme 1). Prior work from thislaboratory demonstrated that the trichloroacetimidate of noviosecarbonate undergoes rapid coupling with phenols to give the desiredα-anomer in high yield.

The boronic acids chosen for this study contain both electronic andsteric moieties that could aid in elucidation of structure-activityrelationships and provide crucial interactions with Lys539 and thesurrounding pocket. Towards this goal, phenylboronic acids (Scheme 2)containing electronegative atoms at the meta- and para-positions wereexplored. In addition, hydrogen bond acceptors were included at theselocations to provide potential hydrogen bonding interactions with theprotonated form of Lys539. To serve as controls, hydrophobic groups (2j,2k) and a tertiary amine (21) were included in this series.

The synthesis of ethyl acetamide side chain containing novologues 11a-p,began with commercially available 2,4-dihydroxybenzaldehyde, 1. The4-phenol of resorcinolic benzaldehyde 1 was protected as thecorresponding benzyl ether 4, (Lee, M.; Gubernator, N. G.; Sulzer, D.;Sames, D., Development of pH-Responsive Fluorescent FalseNeurotransmitters. Journal of the American Chemical Society 2010, 132(26), 8828-8830) and the 2-phenol converted to triflate 5 usingtrifluoromethanesulfonic anhydride and triethylamine (Scheme 3).Compound 5 was subsequently coupled with commercially available arylboronic acids (2a-p) under standard Suzuki conditions to give biarylring systems 6a-p in good yields. Grasa, G. A.; Viciu, M. S.; Huang, J.;Zhang, C.; Trudell, M. L.; Nolan, S. P., Suzuki-Miyaura Cross-CouplingReactions Mediated by Palladium/Imidazolium Salt Systems.Organometallics 2002, 21 (14), 2866-2873; Olson, J. P.; Gichinga, M. G.;Butala, E.; Navarro, H. A.; Gilmour, B. P.; Carroll, F. I., Synthesisand evaluation of 1,2,4-methyltriazines as mGluR5 antagonists. Organic &Biomolecular Chemistry 2011, 9 (11), 4276-4286.

Benzaldehydes 6a-p were converted to the corresponding nitrostyrenes(7a-p), following a Henry reaction with nitromethane and ammoniumacetate. Fuganti, C.; Sacchetti, A., Biocatalytic enantioselectiveapproach to 3-aryl-2-nitropropanols: Synthesis of enantioenriched(R)-5-methoxy-3-aminochroman, a key precursor to the antidepressant drugRobalzotan. Journal of Molecular Catalysis B: Enzymatic 2010, 66 (3-4),276-284; Wood, K.; Black, D. S.; Kumar, N., Ring closing metathesisstrategies towards functionalised 1,7-annulated 4,6-dimethoxyindoles.Tetrahedron 2011, 67 (22), 4093-4102.

Reduction of the nitro and olefin functionalities with lithium aluminumhydride was followed by acylation of the resulting amines to affordacetamides 8a-p in good yields. The benzyl ether of compounds 8a-p wascleaved under hydrogenolysis conditions to afford phenols 9a-p, whichwere coupled with the tricloroacetimidate of noviose carbonate 10¹⁴ inthe presence of a catalytic amount of boron trifluoride etherate.Burlison, J. A.; Neckers, L.; Smith, A. B.; Maxwell, A.; Blagg, B. S.J., Novobiocin: Redesigning a DNA Gyrase Inhibitor for SelectiveInhibition of Hsp90. Journal of the American Chemical Society 2006, 128(48), 15529-15536; Kusuma, B. R.; Peterson, L. B.; Zhao, H.; Vielhauer,G.; Holzbeierlein, J.; Blagg, B. S. J., Targeting the Heat Shock Protein90 Dimer with Dimeric Inhibitors. Journal of Medicinal Chemistry 2011,54 (18), 6234-6253.

The resulting noviosylated biaryl systems were exposed to methanolicammonia to solvolyze the cyclic carbonate and give the desirednovologues (11a-p) in good to moderate yields.

Compounds 41-43 are prepared in an analogous fashion by the protocolshown in Scheme 3.

In some embodiments, the disclosure provides a compound of Formula (I)wherein X₂ together with X₁ form a carbocyclic ring having 3 to 7 ringmembers. For example, two cyclohexene analogues 20a-b were prepared totest the hypothesis regarding the region surrounding the flexible sidechain (Scheme 4). Although these molecules contain the same linkerlength, these analogues contain a bulky cyclohexane tether between thebiaryl ring system and the acetamide.

Synthesis of cyclohexene analogues 20a-b began with the previouslydescribed phenol 4, which was protected as the methoxymethyl (MOM) ether13 (Toda, N. T., K.; Marumoto, S.; Takami, K.; Ori, M.; Yamada, N.;Koyama, K.; Naruto, S.; Abe, K.i; Yamazaki, R.; Hara, T.; Aoyagi, A.;Abe, Y.; Kaneko, T.; Kogen, H, Monoenomycin: a simplified trienomycin Aanalog that manifests anticancer activity. Bioorganic & MedicinalChemistry Letters, ACS ASAP) before the aldehyde of which was convertedto nitrostyrene 14 under Henry conditions. Olson et al., 2011 Id. Theelectron deficient nitrostyrene (14) was subjected to a Diels-Aldercycloaddition with excess butadiene to give an enantiomeric mixture ofcyclohexene derivative 15 in excellent yield. Bryce, M. R.; Gardiner, J.M., Functionalised (+/−)-cephalotaxine analogues. Journal of theChemical Society, Chemical Communications 1989, (16), 1162-1164.

The nitro group of 15 was selectively reduced to the amine via zinc dustand acidic isopropanol, (Brandt, G. E. L.; Blagg, B. S. J.,Monoenomycin: a simplified trienomycin A analog that manifestsanticancer activity. ACS Medicinal Chemistry Letters, ACS ASAP; Pei, Z.;Li, X.; von Geldern, T. W.; Madar, D. J.; Longenecker, K.; Yong, H.;Lubben, T. H.; Stewart, K. D.; Zinker, B. A.; Backes, B. J.; Judd, A.S.; Mulhern, M.; Ballaron, S. J.; Stashko, M. A.; Mika, A. K.; Beno, D.W. A.; Reinhart, G. A.; Fryer, R. M.; Preusser, L. C.; Kempf-Grote, A.J.; Sham, H. L.; Trevillyan, J. M., Discovery of((4R,5S)-5-Amino-4-(2,4,5-trifluorophenyl)cyclohex-1-enyl)-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone(ABT-341), a Highly Potent, Selective, Orally Efficacious, and SafeDipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes.Journal of Medicinal Chemistry 2006, 49 (22), 6439-6442) followed byacetylation to afford acetamide 16 in 71% yield over two steps. In orderto construct the biaryl ring system, the MOM-ether was cleaved to givethe phenol, which was then converted to the corresponding triflate, 17.A Suzuki reaction between 17 and 3-fluorophenylboronic acid or3-(trifluoromethyl) phenylboronic acid, yielded biaryl compounds 18a or18b, respectively. Finally, boron trifluoride etherate promoted removalof the benzyl ether (Andrieux, C. P.; Farriol, M.; Gallardo, I.;Marquet, J., Thermodynamics and kinetics of homolytic cleavage ofcarbon-oxygen bonds in radical anions obtained by electrochemicalreduction of alkyl aryl ethers. Journal of the Chemical Society, PerkinTransactions 2 2002, (5), 985-990) on compounds 18a-b and gave phenols19a-b. Lewis acid-catalyzed noviosylation of 19a-b, with activatednoviose carbonate (10), followed by methanolysis, afforded aninseperable mixture of diastereomeric products, 20a-b.

In some embodiments, the disclosure provides compounds of Formula (I)wherein X₃ is CH₂; in other words, wherein the noviose sugar substituentis replaced with a carbocyclic sugar analogue substituent.

In some embodiments, the disclosure provides compounds of Formula (IV),

wherein R′, R″, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, X, X₁, X₂, X₃, Y, Z andZ₁ are as defined for a compound of Formula (I) above. In someembodiments, the disclosure provides a compound of Formula (IV) whereinX₃ is CH₂.

For example, certain compounds are prepared by the synthetic route shownin Scheme 5.

The phenol core intermediate 23 in Scheme 5 can be prepared by thesynthetic route shown in Scheme 6.

In some embodiments, the disclosure provides compounds of Formula (I) orFormula (IV) wherein X₃ is CH₂, Z is CH, and Z₁ is CH. In someembodiments, the disclosure provides compounds of Formula (I) or Formula(IV) wherein X₃ is CH₂, and Z—Z₁ is —C═C—. For example, Scheme 7 shows arepresentative synthesis of a compound of Formula (I) or Formula (IV),where X₃ is CH₂ and or Z—Z₁ is —C═C—, such as compound 36. For example,Scheme 7 shows a representative synthesis of compounds of Formula (I) orFormula (IV), where X₃ is CH₂ and Z is CH, such as compound 37.

In some embodiments, the disclosure provides a compound of Formula (I)or Formula (IV) wherein X₃ is CH₂ and R₆ is alkyl. A representativesynthetic route is shown in Scheme 8.

Evaluation of Neuroprotective Efficacy

Upon synthesis of ethyl acetamide side chain novologues 11a-p thatcontain various substitutions on the B-ring (hydrogen bond acceptors,hydrogen bond donors, hydrophobic groups, and a tertiary amine), theirneuroprotective efficacy against glucose-induced toxicity of embryonicdorsal root ganglion (DRG) sensory neuron cultures was evaluated. Asshown in Table 1, meta-substituted acetamide novologues (11b, 11e and11f) showed significant protection against glucotoxicity and werecomparable to that observed with KU-32. Although the correspondingortho- and para-substituted (11c, 11d and 11g) derivatives showedsignificant protection against glucose-induced cell death, they weremodestly less effective than novologues 11b, 11e and 11f. However in thecase of analogues 11i (ortho-OMe) and 11j (meta-OMe) the opposite trendwas observed. Electronegative atoms at the meta-position (F, Cl, CF₃)exhibited greater cytoprotective activity, which is believed to resultfrom favorable interactions with Lys539 in the Hsp90 C-terminal bindingpocket. Consistent with this hypothesis, increasing the size of theelectronegative atom at the meta-position (F to Cl to CF3) resulted in adecrease in neuroprotective activity. Similarly, steric bulk wasdisfavored as well. Analogue 11b (meta-F) was the most cytoprotective(95%±14) compound evaluated.

Electronegative atoms at the ortho- or para-position on ring B (11c, 11dand 11g) manifested activities comparable to the unsubstituted analogue(11a) and were less active than the corresponding meta-substitutedanalogues (11b, 11e and 11f). Although novologues 11d and 11g manifestedprotection against neuronal glucotoxicity, they were less effective thanKU-32 and 11b. Compound (11m) (para-OH), with hydrogen-bond donorcharacteristics at the para position of the B-ring, was also somewhat,but not significantly less protective than the unsubstituted analogue(11a).

TABLE 1 Cell viability data of ethyl acetamide side chain novologues.

% of cell Entry R₁ R₂ R₃ X Y viability ^(a) 11a H H H C C 76% ± 11^(#)11b H F H C C 95% ± 14^(#) 11c H H F C C 75% ± 27^(#) 11d Cl H H C C 71%± 21^(#,*) 11e H Cl H C C 90% ± 23^(#) 11f H CF₃ H C C 83% ± 16^(#) 11gH H CF₃ C C 74% ± 19^(#,*) 11h SMe H H C C 83% ± 40^(#) 11i OMe H H C C92% ± 10^(#) 11j H OMe H C C 78% ± 34^(#) 11k H Me H C C 82% ± 30^(#)11l H CH₂-N- H C C 83% ± 26^(#) morpholine 11m H H OH C C 67% ± 10* 11nH —OCH₂O— C C 83% ± 18^(#) 11o H H H N C 61% ± 7* 11p H H H C N 81% ±12^(#)

On the other hand, hydrogen bond acceptors at the para-position (11c and11g) protected against glucose-induced neuronal death but did notdisplay significantly increased protection compared to the novologuecontaining a para-position hydrogen bond donor (11m). ^(a)In thepresence of 1 μM of each novologue+20 mM excess glucose. Viability inthe presence of 20 mM excess glucose+DMSO was 54%±2 and 86%±2 in thepresence of glucose+1 μM KU-32. #, p<0.05 versus glucose+DMSO; * p<0.05versus glucose+KU-32 (n=6-24) per novologue.

Pyridine-containing analogues (11o-p) were also synthesized andevaluated for neuroprotective activity. The 3-pyridine analogue (11o)was unable to protect against glucose-induce toxicity and was alsosignificantly less protective than the corresponding 4-pyridineanalogue, 11p, KU-32, and the unsubstituted phenyl analogue, 11a.Although the 4-pyridine-containing analogue (11p) demonstrated amodestly improved neuroprotective activity when compared to the simplephenyl analogue 11a, this difference in efficacy was not significant.

Neuroprotective activity was also determined for thecyclohexene-containing novologues (20a-b) that contain the fluoro ortrifluoromethane substituent at the meta-position of ring B. In general,cyclohexene-containing analogues 20a-b were less efficacious than thecorresponding derivatives that contain a flexible side chain (11b versus20a, and 11f versus 20b). Although not statistically different,novologue 20a (meta-F) exhibited slightly better cytoprotective activitythan analogue 20b (meta-CF₃), which follows the same trend observed forflexible acetamide-containing compounds (11b versus 11f). Although thesedata are inconsistent with our hypothesis that accommodation of thehydrophobic pocket would improve efficacy, the cyclohexene ring mayexceed the space allowed in this binding cleft.

TABLE 2 Cell viability data of cyclohexene analogues.

Entry R₂ % of cell viability ^(a) 20a F 78% ± 18%^(#) 20b CF₃ 69% ±15%^(#,*) ^(a)In the presence of 1 μM novologue + 20 mM excess glucose.Viability in the presence of 20 mM excess glucose + DMSO was 54% ± 2 and86% ± 2 in the presence of glucose + 1 μM KU-32. #,p<0.05 versus glucose| DMSO; *p<0.05 versus glucose | KU-32 (n = 8) per novologue.

The data in Table 1 clearly support that the majority of novologuessynthesized decrease neuronal toxicity induced by hyperglycemic stress.Although some of these compounds appear more effective than KU-32 at 1μM, the differences were relatively minor. Therefore, to furtherscrutinize their efficacy, compounds exhibiting high neuroprotectiveactivity were further evaluated for determination of EC₅₀ values. Sincethe difference in efficacy for novologues with meta-F and meta-CF₃substitutions on 11b and 11f were not significantly different from KU-32or each other at 1 μM, the EC₅₀ values for these compounds weredetermined alongside 11h, 11l, 11n, and 11o. As shown in FIG. 4, EC₅₀values were significantly improved upon closer inspection and cleardistinctions were obtained. Novologue 11b exhibited an EC₅₀ value(13.0±3.6 nM) that was approximately 14-fold lower than KU-32(240.2±42.5 nM) or 11f (187.7±43.5 nM). Similar results were alsoobserved for novologue 11n, which exhibited an EC₅₀ value of 18.4±3.2nM. In contrast, novologue 11h which manifested similar efficacy toKU-32 at 1 μM, exhibited an EC₅₀ of 384±108 nM, approximately 1.6-foldgreater than KU-32.

The data in FIG. 4 demonstrate that novologues 11b and 11n aresurprisingly more cytoprotective than the initial lead compound, KU-32.Since it was previously shown that the cytoprotective activitymanifested by KU-32 requires Hsp70, the ability of 11b and 11n to induceHsp70 was determined relative to KU-32. Increasing concentrations ofKU-32, 11n, and 11b were incubated with DRG sensory neurons for 24 hoursbefore the cells were subjected to 4 hours of glucotoxic stress. Hsp70levels were examined by performing immunoblot analysis with the cellularlysates (FIG. 5). 11n and 11b induced Hsp70 levels at similarconcentrations (10 nM) as those needed for neuroprotection. Althoughcorrelative, these data provide a clear link between neuroprotection andthe ability of 11b and 11n to induce the heat shock response asexemplified by Hsp70 levels.

Through systematic replacement of substituents on the novologue B-ring(see Table 2), compound 11b was identified as a neuroprotective agentthat surprisingly exhibited ˜14-fold greater efficacy againstglucose-induced toxicity than the lead compound, KU-32. Theconcentration of 11b needed to manifest neuroprotective activitycorrelated well with its ability to induce Hsp70 levels, and thereforelinking cytoprotection to Hsp70 induction. When combined, these datademonstrate the rationally-designed novologue scaffold provides apromising platform on which diversification of the B-ring can lead tocompounds that exhibit better neuroprotective activities.

In one embodiment, the disclosure provides a compound orpharmaceutically acceptable salt according to Formula (I):

wherein

R₁ is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl, alkynyl,carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino,alkoxy, halo, trifluoromethyl, sulfanyl, sulfenyl, sulfonyl, or ether;

R₂ is hydrogen, halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl,alkynyl, carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic,or —R₉—OR₁₀, wherein R₉ is a covalent bond or alkyl, and R₁₀ ishydrogen, alkyl, C-amido or acyl; or R₂ together with R₃ and the atomsto which they are attached form a carbocyclic ring with 5 to 7 ringmembers or a heterocyclic ring having 4 to 8 ring members with at leastone heteroatom selected from oxygen or nitrogen;

R₃ is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl,or —R₁₁—O—R₁₂, wherein R₁₁ is a covalent bond or alkyl, and R₁₂ isalkyl, C-amido or acyl; or R₃ together with R₂ and the atoms to whichthey are attached form a carbocyclic ring with 5 to 7 ring members or aheterocyclic ring having 4 to 8 ring members with at least oneheteroatom selected from oxygen or nitrogen;

R₄ is hydrogen, hydroxy, alkyl, arylalkoxy, carboxyl, —R₁₃—O—R₁₄, or—R₁₃-R₁₅; and wherein R₁₃ is a covalent bond or alkyl, and R₁₄ ishydrogen, C-amido or acyl, and R₁₅ is N-amido, —POR₁₆R₁₇—SO₂R₁₈, orsulfonamido, and wherein R₁₆, R₁₇, R₁₈ are independently alkoxy;

R₅ is hydrogen, hydroxy, alkyl, arylalkoxy, alkenyl, alkynyl, aryl, oraralkyl;

R₆ is hydrogen, hydroxy, sulfanyl, alkyl, alkenyl, alkynyl, aryl,arylalkyl, alkoxy, aryloxy, arylalkoxy or a heterocyclic ring having 4to 8 ring members with at least one heteroatom selected from oxygen ornitrogen;

R₇ is hydrogen, hydroxyl, arylalkoxy, alkyl, acyl, carboxyl or absent;

R₈ is hydrogen, hydroxyl, or arylalkoxy;

R₂₂ is hydrogen, hydroxy, amino, amido, cyano, alkoxy, halogen,trifluoroalkyl, alkyl, alkenyl, alkynyl, ester, nitro, carboxyl,aralkyl, aryl, carbocyclic, heterocyclic, trifluoromethyl, sulfonyl,sulfanyl, sulfenyl, ether, R₂₅—OR₂₆, or R₂₅—NR₂₆; where R₂₅ is acovalent bond or alkyl and R₂₆ is a hydrogen, alkyl, C-amido, or acyl;

R₂₃ is hydrogen, hydroxy, amino, amido, cyano, alkoxy, halogen,trifluoroalkyl, alkyl, alkenyl, alkynyl, ester, nitro, carboxyl,aralkyl, aryl, carbocyclic, heterocyclic, trifluoromethyl, sulfonyl,sulfanyl, sulfenyl, ether, R₂₇—OR₂₈, or R₂₇—NR₂₈; where R₂₇ is acovalent bond or alkyl and R₂₈ is a hydrogen, alkyl, C-amido, or acyl;or R₂₃ together with R₂₄ and the atoms to which they are attached form acarbocyclic ring with 5 to 7 ring members or a heterocyclic ring having4 to 8 members with at least one heteroatom selected from oxygen ornitrogen;

R₂₄ is hydrogen, hydroxy, amino, amido, cyano, alkoxy, halogen,trifluoroalkyl, alkyl, alkenyl, alkynyl, ester, nitro, carboxyl,aralkyl, aryl, carbocyclic, heterocyclic, trifluoromethyl, sulfonyl,sulfanyl, sulfenyl, ether, R₂₉—OR₃₀, or R₂₉—NR₃₀; where R₂₉ is acovalent bond or alkyl and R₃₀ is a hydrogen, alkyl, C-amido, or acyl;or R₂₄ together with R₂₃ and the atoms to which they are attached form acarbocyclic ring with 5 to 7 ring members or a heterocyclic ring having4 to 8 members with at least one heteroatom selected from oxygen ornitrogen;

X₁ is —CHR₁₉— or —CR₁₉═, and wherein R₁₉ is selected from hydrogen,halo, alkyl, alkenyl, or alkynyl; or X₂ together with X₁ form acarbocyclic ring having 3 to 7 ring members; or wherein X₁—X₂ is —C≡C—;

X₂ is —CHR₂₀— or ═CR₂₀—, and wherein R₂₀ is selected from hydrogen,halo, alkyl, alkenyl, or alkynyl; or X₂ together with X₁ form acarbocyclic ring having 3 to 7 ring members; or wherein X₁—X₂ is —C≡C—;

X₃ is O or CH₂;

X is ═CR₂₁— or ═N—, wherein R₂₁ is hydrogen, halo, trifluoromethyl,alkyl, alkenyl, alkynyl, alkoxy, or hydroxy;

R′ is H or alkyl;

R″ is alkyl, alkoxy, haloalkyl, alkylcycloalkyl or alkylamidoalkyl;

Y is ═CR₃— or ═N—;

Z is CH or Z—Z₁ is —C═C—;

Z₁ is CH, O, S, N, or Z—Z₁ is —C═C—; and

n is 0, 1, 2, or 3.

In some embodiments, the disclosure provides compounds of Formula (II):

wherein R₁, R₂, R₃, X and Y are defined as above.

In another embodiment, the disclosure provides a compound or salt offormula (II) wherein R₁ is hydrogen, halo, hydroxy, trifluoroalkyl,alkoxy, or sulfanyl;

R₂ is hydrogen, halo, hydroxy, trifluoroalkyl, alkoxy, sulfanyl, oralkyl, or R₂ together with R₃ and the atoms to which they are attachedform a carbocyclic ring with 5 to 7 ring members or a heterocyclic ringhaving 4 to 8 ring members with at least one heteroatom selected fromoxygen or nitrogen;

R₃ is hydrogen, halo, hydroxy, trifluoroalkyl, alkoxy, sulfanyl, alkyl;or R₃ together with R₂ and the atoms to which they are attached form acarbocyclic ring with 5 to 7 ring members or a heterocyclic ring having4 to 8 ring members with at least one heteroatom selected from oxygen ornitrogen;

X is ═CR₂₁— or ═N—, wherein R₂₁ is hydrogen, halo, or trifluoromethyl;and

Y is ═CR₃— or ═N—.

In some embodiments, the disclosure provides compounds of Formula (III),wherein R₁, R₂, R₃, R₂₂, R₂₃, R₂₄, X and Y are defined as above.

In some embodiments, the disclosure provides a compound of Formula (III)wherein one of R₂₂, R₂₃, and R₂₄ is not H.

In a specific embodiments, the neuroprotective compound is selectedfrom:

-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11a);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11b);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11c);-   N-(2-(2′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11d);-   N-(2-(3′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11e);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11f);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11g);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2′-(methylthio)-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11h);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11i);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11j);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-methyl-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11k);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(morpholinomethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11l);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11m);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (11m):-   N-(2-(benzo[d][1,3]dioxol-5-yl)-4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)phenethyl)acetamide    (11n):-   N-(4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-(pyridin-3-yl)phenethyl)acetamide    (11o);-   N-(4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-(pyridin-4-yl)phenethyl)acetamide    (11p);-   N-(4′-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3″-fluoro-1,2,3,6-tetrahydro-[1,1′:2′,    1″-terphenyl]-2-yl)acetamide (20a);-   N-(4″-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3″-(trifluoromethyl)-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide    (20b);-   N-(2-(5-((4-(benzyloxy)cyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (24);-   N-(2-(5-((4-(benzyloxy)cyclohex-2-en-1-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (36);-   N-(2-(5-((4-(benzyloxy)-2,3-dihydroxycyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (37);-   N-(2-(5-((4-(tert-butyl)cyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (39);-   N-(2-(3′-fluoro-5-((4-(piperidin-4-yl)cyclohexyl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (40);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-6-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (41);-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-3-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (42); and-   N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-4-methyl-[1,1′-biphenyl]-2-yl)ethyl)acetamide    (43).

Several of the compounds of the present invention have been shown toinhibit Hsp90 in vitro. As such, it is contemplated that therapeuticallyeffective amounts of the compounds of the present invention will beuseful as neuroprotective agents that result in at least a 10%enhancement of cell viability compared to control over a given timeperiod and under certain conditions, for example, such asglucose-induced toxicity in vitro or under a diabetic condition in vivo.

In the context of neuroprotection, it is contemplated that some of thecompounds of the present invention may be used with other Hsp90inhibitors and/or neuroprotective agents.

The following examples are provided to illustrate the present inventionand are not intended to limit the scope thereof. Those skilled in theart will readily understand that known variations of the conditions andprocesses of the following preparative procedures can be used to preparethese compounds.

The present invention is directed to the use of therapeuticallyeffective amount of one or more of the compounds disclosed herein totreat and/or prevent a neurodegenerative disorder such as diabeticperipheral neuropathy and/or to provide neuroprotection.

Compositions of the Present Invention

According to another aspect, the present invention provides apharmaceutical composition, which comprises a therapeutically-effectiveamount of one or more compounds of the present invention or apharmaceutically-acceptable salt, ester or prodrug thereof, togetherwith a pharmaceutically-acceptable diluent or carrier. Thepharmaceutical compositions provide neuroprotection and used to treatand/or prevent neurodegenerative disorders.

The compositions may be formulated for any route of administration, inparticular for oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, or intranasal administration. The compositions may beformulated in any conventional form, for example, as tablets, capsules,caplets, solutions, suspensions, dispersions, syrups, sprays, gels,suppositories, patches, and emulsions.

Accordingly, the compounds of the present invention are useful in thetreatment or alleviation of neurodegenerative disorders, such asAlzheimer's disease, Parkinson's disease, Lou Gehrig's disease, ormultiple sclerosis, to name a few, not to mention central or peripheralnervous system damage, dysfunction, or complications involving samestemming from edema, injury, or trauma. Such damage, dysfunction, orcomplications may be characterized by an apparent neurological,neurodegenerative, physiological, psychological, or behavioralaberrations, the symptoms of which can be reduced by the administrationof a therapeutically effective amount of the compounds of the presentinvention.

The following examples are provided for further illustration of thepresent invention, and do not limit the invention.

EXAMPLES Example 1. Preparation of Embryonic Dorsal Root Ganglion (DRG)Neuron Cultures

DRG from embryonic day 15-18 Sprague Dawley rat pups were harvested intoLeibovitz's L15 medium (L15) and dissociated with 0.25% trypsin for 30min at 37° C. The ganglia were sedimented at 1,000×g for 5 min,resuspended in growth media [phenol red free Neurobasal medium (Gibco,Grand Island, N.Y.) containing 25 mM glucose, 1×B-27 additive, 50 ng/mlNGF (Harlan Bioscience, Indianapolis, Ind.), 4 mM glutamine, 100 U/mLpenicillin and 100 [μg/mL streptomycin] and triturated with afire-polished glass pipette. The cells were cultured on collagen-coated(0.1 mg/mL collagen followed by overnight air drying in a laminar flowhood) black-walled 96-well plates (Corning Incorporated Corning, N.Y.)at a seeding density of 2-3×10⁴ cells per well. DRG neurons were re-fedthe next day with fresh growth media containing 40 μM fluorodeoxyuridineand 10 μM cytosine (3-D-arabinoside (both from Sigma Aldrich, St. Louis,Mo.) for 2 days to remove proliferating cells. Experiments wereperformed on DRG neurons on the third day in culture after placing thecells in fresh growth medium.

Example 2. Glucotoxicity Assay

Immature DRG are susceptible to hyperglycemia-induced death. Vincent, A.M.; Kato, K.; McLean, L. L.; Soules, M. E.; Feldman, E. L., SensoryNeurons and Schwann Cells Respond to Oxidative Stress by IncreasingAntioxidant Defense Mechanisms. Antioxid Redox Signal 2009, 11, 425-438.Therefore, an additional 20 mM glucose was added to the growth medium ofExample 1 (yielding a total of 45 mM glucose) for 4 hours. Preliminaryexperiments found that 20 mM excess glucose for 4 hrs was sufficient toinduce a reproducible 40-50% loss in neuronal viability. As a result,the toxicity induced by the acute change in glucose concentration makesit a useful model for drug screening. Urban, M. J.; Li, C.; Yu, C.; Lu,Y.; Krise, J. M.; McIntosh, M. P.; Raj ewski, R. A.; Blagg, B. S. J.;Dobrowsky, R. T., Inhibiting Heat Shock Protein 90 Reverses SensoryHypoalgesia in Diabetic Mice. ASN Neuro 2010, 2, e00040 DOI: 189-199;Vincent, A. M.; Stevens, M. J.; Backus, C.; McLean, L. L.; Feldman, E.L., Cell culture modeling to test therapies againsthyperglycemia-mediated oxidative stress and injury. Antioxid RedoxSignal 2005, 7 (11-12), 1494-506.

Given the short time frame that the neurons are grown in vitro, they arenot pure neuronal cultures but instead, highly enriched. Importantly,the contaminating SCs that remain in the culture are resistant toglucose-induced death as we and others have reported previously.Vincent, A. M.; Kato, K.; McLean, L. L.; Soules, M. E.; Feldman, E. L.,Sensory Neurons and Schwann Cells Respond to Oxidative Stress byIncreasing Antioxidant Defense Mechanisms. Antioxid Redox Signal 2009,11, 425-438; Zhang, L.; Yu, C.; Vasquez, F. E.; Galeva, N.; Onyango, I.;Swerdlow, R. H.; Dobrowsky, R. T., Hyperglycemia alters the schwann cellmitochondrial proteome and decreases coupled respiration in the absenceof superoxide production. J Proteome Res 2010, 9 (1), 458-71.

Unfortunately, the use of highly purified cultures is problematic sincethe cells extend neurites and establish connections with each other,thus becoming resistant to hyperglycemia-induced death. Yu, C.; Rouen,S.; Dobrowsky, R. T., Hyperglycemia and downregulation of caveolin-1enhance neuregulin-induced demyelination. Glia 2008, 56, 877-887.

DRG neurons were incubated overnight with the test compounds in thepresence of Neurobasal medium, 50 ng/ml NGF and antibiotics only. Inorder to monitor the efficiency of the compounds in protecting DRGneurons against glucotoxicity, Calcein AM (Invitrogen, Carlsbad, Calif.)was utilized to measure cell viability. Hydrolysis of calcein AM to afluorescent product can only occur in live cells. Excess glucose wasadded to the cultures for 4 hrs and cell viability was measured byincubating the cells with 2 μM calcein AM for 30 min in the dark at 37°C. Fluorescence was then measured using a plate reader with excitationand emission wavelengths set to 485 nm and 520 nm, respectively. Thearbitrary fluorescence readings were normalized to the total amount ofprotein from each respective well of the neuronal cultures. The proteinconcentrations in each well were determined using the DC protein assay(Bio-Rad). Significant differences in the efficacy of the novologues forincreasing cell viability were determined using a Kruskal-Wallisnon-parametric ANOVA and Dunn's post-test.

Example 3. Chemistry General-NMR

¹H NMR were recorded at 400 or 500 MHz (Bruker DRX-400 Bruker with aH/C/P/F QNP gradient probe) spectrometer and ¹³C NMR spectra wererecorded at 125 MHz (Bruker DRX 500 with broadband, inverse tripleresonance, and high resolution magic angle spinning HR-MA probespectrometer); chemical shifts are reported in δ (ppm) relative to theinternal reference chloroform-d (CDCl₃, 7.27 ppm).

Example 4. Chemistry General-Mass Spectroscopy and HPLC

FAB (HRMS) spectra were recorded with a LCT Premier (Waters Corp.,Milford, Mass.).

The purity of all compounds was determined to be >95% as determined by¹H NMR and ¹³C NMR spectra, unless otherwise noted. The most active 5compounds were verified for >95% purity by HPLC analyses. TLC wasperformed on glass backed silica gel plates (Uniplate) with spotsvisualized by UV light. All solvents were reagent grade and, whennecessary, were purified and dried by standard methods. Concentration ofsolutions after reactions and extractions involved the use of a rotaryevaporator operating at reduced pressure.

Example 5. Synthesis of 5-(benzyloxy)-2-formylphenyltrifluoromethanesulfonate (3)

A solution of phenol 2 (11.2 g, mmol) in anhydrous DCM (245 mL) wasstirred at 0° C. and triethylamine (10.2 mL, 73.5 mmol) was addedfollowed by triflic anhydride (13.8 mL, 63.5 mmol) over 5 minutes. Uponcompletion the reaction was quenched by addition of water (50 mL),washed with saturated aqueous NaCl solution, dried (Na₂SO₄), filteredand concentrated. The residue was purified by column chromatography(SiO₂, 4:1, Hex:EtOAc) to afford triflate 3 as a yellow oil (8.4 g, 23.6mmol, 48%). Immediately used in Suzuki coupling reactions.

Example 6. General Procedure for Suzuki Coupling Reaction of Triflate 3and Boronic Acids 2a-p 5-(benzyloxy)-[1,1′-biphenyl]-2-carbaldehyde (6a)

Triflate 5 (0.246 g, 0.68 mmol), phenylboronic acid 2a (92 mg, 0.75mmol), tetrakis(triphenylphosphine)palladium(0) (70.4 mg, 0.068 mmol)and K₂CO₃ (0.169 g, 1.2 mmol) was dissolved in DMF (6.8 mL) under argonatmosphere in a sealed tube. The resulting reaction mixture was sealedand heated to reflux for 16 h. The reaction was cooled to RT, quenchedwith saturated sodium bicarbonate, extracted with EtOAc (3×5 mL), washedwith saturated aqueous sodium chloride, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product was purified by columnchromatography (SiO₂, 3:1, Hex:EtOAc) to afford 6a (0.16 g, 0.56 mmol,82%) as an amorphous solid. ¹H NMR (400 MHz, CDCl₃) δ 9.90 (s, 1H), 8.08(d, J=8.7 Hz, 1H), 7.55-7.34 (m, 10H), 7.11 (d, J=8.7 Hz, 1H), 7.0 3 (d,J=2.4 Hz, 1H), 5.19 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 191.2, 162.8,148.6, 137.8, 136.0, 130.0, 128.8, 128.4, 127.6, 116.3, 114.7, 70.4;HRMS (FAB) m/z: [M+Na⁺] for C₂₀H₁₆O₂Na, calcd, 311.1042; found,311.1046.

5-(benzyloxy)-3′-fluoro-[1,1′-biphenyl]-2-carbaldehyde (6b)

Using 3-flourophenylboronic acid. ¹H NMR (500 MHz, CDCl₃) δ 9.85 (d,J=0.7 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.49-7.33 (m, 6H), 7.20-7.13 (m,2H), 7.13-7.08 (m, 2H), 7.03 (d, J=2.5 Hz, 1H), 5.15 (s, 2H); ¹³C NMR(125 MHz, CDCl₃) δ 190.7, 162.9, 161.7, 147.2, 140.1, 136.0, 130.5,129.0, 128.6, 127.8, 126.0, 117.1, 116.9, 116.4, 115.5, 115.1, 70.6;HRMS m/z: [M+Na⁺] for C₂₀H₁₅FO₂Na, calcd, 329.0948; found, 329.0952.

5-(benzyloxy)-4′-fluoro-[1,1′-biphenyl]-2-carbaldehyde (6c)

Using 4-Flourophenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ 9.84 (s,1H), 8.06 (dd, J=8.7, 1.0 Hz, 1H), 7.49-7.40 (m, 4H), 7.40-7.32 (m, 3H),7.21-7.13 (m, 2H), 7.12-7.06 (dd, J=8.0, 2.5 Hz, 1H), 7.03 (d, J=2.2 Hz,1H), 5.17 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 190.9, 162.8, 147.4,136.0, 131.7, 131.6, 130.5, 128.8, 128.5, 127.7, 127.6, 116.5, 115.6,115.4, 114.7, 70.4; HRMS m/z: [M+Na⁺] for C₂₀H₁₅FO₂Na, calcd, 329.0948;found, 329.0944.

5-(benzyloxy)-2′-chloro-[1,1′-biphenyl]-2-carbaldehyde (6d)

Using 2-Chlorophenylboronic acid. ¹H NMR (500 MHz, CDCl₃) δ 9.70 (s,1H), 8.08 (d, J=8.7 Hz, 1H), 7.55-7.49 (m, 1H), 7.49-7.32 (m, 8H),7.17-7.12 (dd, J=8.6, 2.5 Hz, 1H), 6.99 (d, J=2.6 Hz, 1H), 5.16 (s, 2H);¹³C NMR (125 MHz, CDCl₃) δ 190.3, 162.9, 145.1, 136.8, 135.9, 133.5,131.6, 130.0, 129.8, 129.6, 128.8, 128.4, 127.6, 127.6, 126.9, 116.7,115.1, 70.4; HRMS m/z: [M+Na⁺] for C₂₀H₁₅ClO₂Na, calcd, 345.0658; found,345.0653.

5-(benzyloxy)-3′-chloro-[1,1′-biphenyl]-2-carbaldehyde (6e)

Using 3-Chlorophenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ 9.85 (s,1H), 8.04 (d, J=8.7 Hz, 1H), 7.49-7.33 (m, 8H), 7.26 (m, 1H), 7.13-7.07(dd, J=8.3, 2.8 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 5.17 (s, 2H); ¹³C NMR(100 MHz, CDCl₃) δ 190.4, 162.8, 146.8, 139.7, 135.9, 134.5, 130.5,129.8, 129.7, 128.8, 128.5, 128.4, 128.3, 127.6, 127.5, 116.3, 115.0,70.4; HRMS m/z: [M+Cl⁻] for C₂₀H₁₅C₁₂O₂, calcd, 341.0505; found,341.0508.

5-(benzyloxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbaldehyde (6f)

Using 3-(Trifluoromethyl)phenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ9.82 (s, 1H), 8.05 (m, 1H), 7.72 (m, 1H), 7.67-7.64 (td, J=1.6, 0.8 Hz,1H), 7.64-7.53 (m, 2H), 7.50-7.35 (m, 5H), 7.15-7.11 (dd, J=8.7, 2.2 Hz,1H), 6.96 (d, J=2.5 Hz, 1H), 5.19 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ190.4, 163.0, 146.8, 138.8, 135.9, 133.4, 131.0, 130.9, 129.0, 129.0,128.6, 127.8, 127.6, 126.6, 126.5, 125.2, 116.7, 115.2, 70.6; HRMS m/z:[M+Na⁺] for C₂₁H₁₅F₃O₂Na, calcd, 379.0922; found, 379.0926.

5-(benzyloxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbaldehyde (6 g)

Using 4-(Trifluoromethyl)phenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ9.84 (s, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.55-7.49(m, 2H), 7.49-7.34 (m, 6H), 7.17-7.12 (dd, J=9.1, 2.2 Hz, 1H), 6.98 (d,J=2.5 Hz, 1H), 5.19 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 190.2, 162.9,146.7, 141.7, 135.9, 130.8, 130.3, 128.9, 128.6, 127.7, 127.5, 125.5,125.4, 122.8, 116.6, 115.1, 70.5; HRMS m/z: [M+H⁺] for C₂₁H₁₆F₃O₂,calcd, 357.1097; found, 357.1096.

5-(benzyloxy)-2′-(methylthio)-[1,1′-biphenyl]-2-carbaldehyde (6h)

Using 2-(Methylthio)phenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ 9.62(s, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.47-7.32 (m, 6H), 7.30-7.23 (m, 2H),7.24-7.20 (m, 1H), 7.13-7.09 (m, 1H), 6.93-6.90 (m, 1H), 5.17 (s, 2H),2.36 (d, J=1.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 190.8, 163., 146.3,138.4, 136.2, 136.1, 130.4, 129.5, 129.1, 128.8, 128.4, 127.8, 127.7,124.7, 124.6, 116.4, 115.3, 70.4, 15.6; HRMS m/z: [M+H⁺] forC₂₁H₁₈O₂SNa, calcd, 357.0920; found, 357.0923.

5-(benzyloxy)-2′-methoxy-[1,1′-biphenyl]-2-carbaldehyde (6i)

Using 2-Methoxyphenylboronic acid. ¹H NMR (500 MHz, CDCl₃) δ 9.73 (s,1H), 8.07 (d, J=8.7 Hz, 1H), 7.48-7.39 (m, 5H), 7.37 (d, J=6.5 Hz, 1H),7.32-7.27 (m, 1H), 7.13-7.07 (m, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.98-6.95(dd, J=2.4, 1.1 Hz, 1H), 5.15 (s, 2H), 3.75 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 191.5, 163.1, 156.6, 144.5, 136.2, 131.4, 130.1, 129.2, 128.8,128.4, 127.9, 127.7, 126.8, 121.0, 116.9, 114.5, 110.8, 70.3, 55.5; HRMSm/z: [M+H⁺] for C₂₁H₁₉O₃, calcd, 319.1329; found, 319.1333.

5-(benzyloxy)-3′-methoxy-[1,1′-biphenyl]-2-carbaldehyde (6j)

Using 3-Methoxyphenylboronic acid. ¹H NMR (400 MHz, CDCl₃) δ 9.93 (s,1H), 8.06 (d, J=9.0 Hz, 1H), 7.52-7.35 (m, 6H), 7.10 (d, J=8.6 Hz, 1H),7.05-6.93 (m, 4H), 5.20 (s, 2H), 3.89 (s, 3H); HRMS m/z: [M+Na⁺] forC₂₁H₁₈O₃Na, calcd, 341.1154; found, 341.1150.

5-(benzyloxy)-3′-methyl-[1,1′-biphenyl]-2-carbaldehyde (6k)

Using 3-Methylphenylboronic acid. ¹H NMR (500 MHz, CDCl₃) δ 9.85 (d,J=0.9 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.49-7.39 (m, 3H), 7.39-7.32 (m,2H), 7.27 (d, J=8.1 Hz, 1H), 7.22-7.16 (m, 2H), 7.09-7.05 (ddd, J=8.8,2.6, 0.9 Hz, 1H), 6.98 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 2.43 (s, 3H);¹³C NMR (125 MHz, CDCl₃) δ 191.4, 162.8, 148.9, 138.3, 137.9, 136.2,130.9, 130.1, 129.2, 128.9, 128.5, 128.5, 127.8, 127.3, 116.3, 114.8,70.5, 21.7; HRMS m/z: [M+H⁺] for C₂₁H₁₈O₂Na, calcd, 325.1205; found,325.1217.

5-(benzyloxy)-3′-(morpholinomethyl)-[1,1′-biphenyl]-2-carbaldehyde (61)

Using 3-(4-Morpholinomethyl)phenylboronic acid pinacol ester. ¹H NMR(400 MHz, CDCl₃) δ 9.87 (s, 1H), 8.83 (d, J=8.7 Hz, 1H), 7.47-7.31 (m,7H), 7.32-7.24 (m, 1H), 7.12-7.04 (dd, J=8.7, 2.5 Hz, 1H), 7.05 (d,J=2.5 Hz, 1H), 5.17 (s, 2H), 3.79-3.68 (t, J=4.6 Hz, 4H), 3.56 (s, 3H),2.49 (d, J=6.5 Hz, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 191.0, 162.7, 148.5,138.3, 137.8, 136.0, 130.7, 130.2, 129.1, 128.8, 128.4, 127.6, 127.6,116.4, 114.5, 70.4, 67.1, 63.2, 53.7; HRMS m/z: [M+Na⁺] for C₂₅H₂₅NO₃Na,calcd, 410.1726; found, 410.1730.

5-(benzyloxy)-4′-hydroxy-[1,1′-biphenyl]-2-carbaldehyde (6m): Used4-Hydroxyphenylboronic acid.

Partially purified biaryl phenol was treated with TBSCl (1.2 eq.) andimidazole (3 eq.) in DCM and stirred for 2 h at RT. After reaction wascompleted by TLC, the resulting reaction mixture was concentrated. Thecrude product was purified by column chromatography (SiO₂, 4:1,Hex:EtOAc) to afford 6m (94%) as an amorphous solid. ¹H NMR (500 MHz,CDCl₃) δ 9.89 (s, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.52-7.33 (m, 5H), 7.26(dd, J=6.6, 1.8 Hz, 2H), 7.05 (dd, J=8.7, 2.3 Hz, 1H), 7.02-6.93 (m,3H), 5.17 (s, 2H), 1.05 (s, 9H), 0.29 (s, 6H); ¹³C NMR (125 MHz, CDCl₃)δ 191.2, 162.7, 156.0, 148.4, 136.1, 131.2, 130.6, 130.0, 128.7, 128.3,127.6, 127.5, 120.0, 116.1, 114.3, 70.3, 25.7, 18.3, 4.3; ESI-HRMS m/z:[M+Na]⁺ for C₂₆H₃₀NaO₃Si, calcd, 441.5899, found 441.5896.

2-(benzo[d][1,3]dioxol-5-yl)-4-(benzyloxy)benzaldehyde (6n)

Using 3,4-(Methylenedioxy)phenylboronic acid. ¹H NMR (500 MHz, CDCl₃) δ9.90 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.48-7.39 (m, 4H), 7.39-7.35 (m,1H), 7.06 (d, J=8.6 Hz, 1H), 6.97 (d, J=2.5 Hz, 1H), 6.91-6.86 (m, 2H),6.83-6.79 (m, 1H), 6.03 (s, 2H), 5.15 (s, 2H); ¹³C NMR (125 MHz, CDCl₃)δ 191.2, 162.8, 148.2, 147.9, 147.9, 136.1, 131.6, 130.2, 128.8, 128.4,127.7, 127.6, 124.0, 116.2, 114.5, 110.3, 108.3, 101.5, 70.4; HRMS (FAB)m/z: [M+Na⁺] for C₂₁H₁₆O₄Na, calcd, 355.0941; found, 355.0935.

4-(benzyloxy)-2-(pyridin-3-yl)benzaldehyde (6o)

¹H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 8.65 (dd, 2H, J=5.1, 8.3 Hz),8.01 (d, 1H, J=8.8 Hz), 7.67 (m, 1H), 7.48-7.26 (m, 6H), 7.09 (dd, 1H,J=2.4, 8.7 Hz), 6.93 (d, 1H, J=2.4 Hz), 5.14 (s, 2H); ¹³C NMR (125 MHz,CDCl₃) δ 187.8, 165.3, 160.5, 135.8, 131.2, 129.0, 128.7, 127.8, 120.0,109.5, 102.1, 91.0, 70.8; HRMS (FAB) m/z: [M+H⁺] for C₁₉H₁₆NO₂, calcd,290.1181; found, 290.1177.

4-(benzyloxy)-2-(pyridin-4-yl)benzaldehyde (6p)

¹H NMR (500 MHz, CDCl₃) δ 9.82 (s, 1H), 8.67 (d, J=5.9 Hz, 2H), 8.02 (d,J=8.7 Hz, 1H), 7.49-7.33 (m, 6H), 7.30 (d, J=6.0 Hz, 1H), 7.15-7.10 (dd,J=8.6, 2.6 Hz, 1H), 6.95 (d, J=2.6 Hz, 1H), 5.15 (s, 2H); ¹³C NMR (125MHz, CDCl₃) δ 189.7, 162.9, 149.8, 145.8, 145.2, 135.7, 131.0, 128.8,128.5, 127.6, 127.1, 124.6, 116.3, 115.4, 70.5; HRMS (FAB) m/z: [M+H⁺]for C₁₉H₁₆NO₂, calcd, 290.1181; found, 290.1183.

Example 7. General Procedure for Henry Reaction of Compounds 6a-p(E)-5-(benzyloxy)-2-(2-nitrovinyl)-1,1′-biphenyl (7a)

Nitromethane (1.4 mL) was added to a mixture of aldehyde 6a (0.16 g,0.56 mmol) and ammonium acetate (77 mg, 1.0 mmol) and heated to 50° C.Upon completion (˜15-30 min), the reaction mixture was cooled to RT andpurified without work-up by column chromatography (SiO₂, 3:1, Hex:EtOAc)to afford nitrostyrene 7a as a yellow oil (182 mg, 0.55 mmol, 98%). ¹HNMR (400 MHz, CDCl₃) δ 8.02 (d, J=13.6 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H),7.50-7.35 (m, 10H), 7.31 (d, J=2.1 Hz, 2H), 7.04 (d, J=2.5 Hz, 1H), 5.15(s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 161.8, 146.1, 138.1, 136.4, 136.3,135.5, 131.8 131.7, 129.9, 129.2, 128.8, 128.0, 121.3, 117.3, 116.3,116.0, 115.6, 70.7; HRMS (FAB) m/z: [M+Na⁺] for C₂₁H₁₈NO₃, calcd,332.1281; found, 332.1290.

(E)-5-(benzyloxy)-3′-fluoro-2-(2-nitrovinyl)-1,1′-biphenyl (7b)

¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=13.5 Hz, 1H), 7.65 (d, J=8.7 Hz,1H), 7.49-7.35 (m, 7H), 7.20-7.13 (ddd, J=9.3, 7.9, 2.6 Hz, 1H),7.09-7.03 (m, 2H), 7.02 (d, J=2.8 Hz, 2H), 5.16 (s, 2H); ¹³C NMR (100MHz, CDCl₃) δ 164.0, 161.5, 145.4, 141.4, 137.6, 136.1, 136.0, 130.5,130.4, 129.6, 128.6, 127.7, 125.7, 121.0, 116.9, 116.6, 115.6, 115.4,70.5; HRMS m/z: [M+H⁺] for C₂₁H₁₇FNO₃, calcd, 350.1187; found, 350.1185.

(E)-5-(benzyloxy)-4′-fluoro-2-(2-nitrovinyl)-1,1′-biphenyl (7c)

¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=13.6 Hz, 1H), 7.64 (d, J=8.7 Hz,1H), 7.50-7.34 (m, 6H), 7.32-7.24 (m, 2H), 7.23-7.14 (t, J=8.3 Hz, 2H),7.10-7.00 (m, 2H), 5.17 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 161.5,145.7, 137.8, 136.1, 136.0, 131.5, 131.4, 129.6, 128.9, 128.5, 127.7,121.0, 117.0, 115.9, 115.7, 115.3, 70.4; HRMS m/z: [M+Na⁺] forC₂₁H₁₆FNO₃Na, calcd, 372.1006; found, 372.1011.

(E)-5-(benzyloxy)-2′-chloro-2-(2-nitrovinyl)-1,1′-biphenyl (7d)

¹H NMR (500 MHz, CDCl₃) δ 7.85-7.75 (m, 1H), 7.74-7.66 (m, 1H), 7.55 (m,1H), 7.53-7.34 (m, 8H), 7.31 (d, J=5.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H),7.01 (t, J=2.0 Hz, 1H), 5.20-5.11 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ161.4, 143.8, 137.7, 137.0, 135.9, 133.2, 131.4, 130.0, 130.0, 129.3,128.7, 128.3, 127.6, 127.1, 123.4, 121.5, 117.1, 115.6, 70.3; HRMS m/z:[M+H⁺] for C₂₁H₁₇ClNO₃, calcd, 366.0892; found, 366.0895.

5-(benzyloxy)-3′-chloro-2-(2-nitrovinyl)-1,1′-biphenyl (7e)

¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=13.5 Hz, 1H), 7.64 (d, J=8.8 Hz,1H), 7.50-7.36 (m, 8H), 7.33 (s, 1H), 7.18 (d, J=7.0 Hz, 1H), 7.09-7.04(m, 1H), 7.00 (d, J=2.6 Hz, 1H), 5.17 (s, 2H); ¹³C NMR (125 MHz, CDCl₃)δ 145.1, 141.1, 140.9, 137.4, 136.1, 134.7, 129.9, 129.6, 129.6, 129.5,129.0, 128.8, 128.5, 128.4, 128.0, 127.6, 120.9, 116.9, 115.5, 109.9,70.4; HRMS m/z: [M+Cl⁻] for C₂₁H₁₆Cl₂NO₃, calcd, 400.0513; found,400.0505.

(E)-5-(benzyloxy)-2-(2-nitrovinyl)-3′-(trifluoromethyl)-1,1′-biphenyl(7f)

¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, J=13.5 Hz, 1H), 7.78-7.70 (m, 1H),7.69-7.55 (m, 3H), 7.51-7.34 (m, 7H), 7.13-7.05 (dd, J=8.8, 2.6 Hz, 1H),7.02 (d, J=2.6 Hz, 1H), 5.17 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 161.6,155.7, 152.1, 145.1, 140.6, 140.0, 137.2, 136.4, 136.0, 133.2, 129.7,129.3, 129.0, 128.6, 127.7, 121.0, 117.1, 115.8, 70.6; HRMS m/z: [M+H⁺]for C₂₂H₁₇F₃NO₃, calcd, 400.1161; found, 400.1157.

(E)-5-(benzyloxy)-2-(2-nitrovinyl)-4′-(trifluoromethyl)-1,1′-biphenyl(7g)

Pushed through plug of SiO2. TS1-189: ¹H NMR (400 MHz, CDCl₃) δ7.98-7.90 (m, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.8 Hz, 1H),7.52-7.37 (m, 8H), 7.11 (d, J=8.8 Hz, 1H), 7.04 (s, 1H), 5.19 (s, 2H);¹³C NMR (100 MHz, CDCl₃) δ 161.4, 147.8, 144.9, 144.3, 139.8, 138.6,137.1, 136.4, 135.8, 133.5, 131.2, 129.5, 129.1, 128.8, 128.5, 127.6,124.2, 120.8, 120.4, 117.0, 115.6, 70.4; HRMS m/z: [M+H⁺] forC₂₂H₁₇F₃NO₃, calcd, 400.1155; found, 400.1151.

(E)-(5′-(benzyloxy)-2′-(2-nitrovinyl)-[1,1′-biphenyl]-2-yl)(methyl)sulfane(7h)

¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=13.6 Hz, 1H), 7.62 (d, J=8.6 Hz,1H), 7.45-7.31 (m, 7H), 7.31-7.29 (m, 1H), 7.25-7.19 (t, J=7.2 Hz, 1H),7.13-6.99 (m, 2H), 6.95 (d, J=2.8 Hz, 1H), 5.09 (s, 2H), 2.35 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 161.5, 144.9, 138.0, 137.5, 137.2, 136.1,135.7, 130.0, 129.4, 129.3, 128.8, 128.4, 127.7, 125.0, 124.9, 121.6,117.0, 115.8, 70.3, 15.6; HRMS m/z: [M+K⁺] for C₂₂H₁₉NO₃SK, calcd,416.0718; found, 416.0756.

(E)-5-(benzyloxy)-2′-methoxy-2-(2-nitrovinyl)-1,1′-biphenyl (7i)

¹H NMR (500 MHz, CDCl₃) δ 7.86 (d, J=13.8 Hz, 1H), 7.65 (d, J=8.7 Hz,1H), 7.57-7.34 (m, 7H), 7.24-7.17 (m, 1H), 7.16-6.99 (m, 4H), 5.15 (s,2H), 3.74 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 161.6, 156.4, 143.7,138.8, 136.3, 135.3, 131.4, 130.4, 128.9, 128.4, 127.7, 122.0, 121.1,117.5, 115.1, 111.4, 70.4, 55.6; HRMS m/z: [M+H⁺] for C₂₂H₁₉NO₄, calcd,362.1387; found, 362.1389.

(E)-5-(benzyloxy)-3′-methoxy-2-(2-nitrovinyl)-1,1′-biphenyl (7j)

¹H NMR (500 MHz, CDCl₃) δ 8.04 (d, J=13.6 Hz, 1H), 7.62 (d, J=9.5 Hz,1H), 7.46-7.37 (m, 6H), 7.07-7.02 (m, 3H), 7.02-6.97 (ddd, J=8.2, 2.6,0.9 Hz, 1H), 6.88-6.84 (m, 1H), 6.84-6.80 (dd, J=2.6, 1.6 Hz, 1H), 5.15(s, 2H), 3.85 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 161.5, 159.8, 146.8,140.6, 138.2, 136.2, 135.9, 129.9, 129.5, 129.0, 128.6, 127.7, 122.3,121.1, 116.8, 115.4, 115.4, 114.1, 70.5, 55.6; HRMS m/z: [M+Na⁺] forC₂₂H₁₉NO₄Na, 384.1212; found, 384.1218.

(E)-5-(benzyloxy)-3′-methyl-2-(2-nitrovinyl)-1,1′-biphenyl (7k)

¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=13.6 Hz, 1H), 7.62 (m, 1H),7.48-7.39 (m, 7H), 7.39-7.33 (t, J=7.7 Hz, 1H), 7.14-7.07 (m, 2H),7.05-6.99 (m, 2H), 5.15 (s, 2H), 2.43 (s, 3H); ¹³C NMR (125 MHz, CDCl₃)δ 138.4, 135.8, 130.4, 129.5, 129.3, 128.9, 128.7, 128.5, 127.8, 127.8,126.9, 121.1, 116.8, 115.3, 77.5, 77.4, 77.2, 77.0, 70.5 21.7; HRMS m/z:[M+Na⁺] for C₂₂H₁₉NO₃Nalcd, 368.1263; found, 368.1257.

(E)-4-((5′-(benzyloxy)-2′-(2-nitrovinyl)-[1,1′-biphenyl]-3-yl)methyl)morpholine(7l)

¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=13.6 Hz, 1H), 7.63 (d, J=9.5 Hz,1H), 7.48-7.33 (m, 8H), 7.33 (d, J=1.7 Hz, 1H), 7.23-7.20 (dd, J=6.7,1.8 Hz, 1H), 7.08-6.99 (m, 2H), 5.15 (d, J=1.6 Hz, 2H), 3.79-3.67 (t,J=4.1 Hz, 4H), 3.56 (s, 2H), 2.55-2.40 (dd, J=5.7, 3.4 Hz, 4H); ¹³C NMR(100 MHz, CDCl₃) δ 161.5, 146.9, 139.2, 138.5, 138.1, 136.1, 135.8,130.6, 129.5, 129.3, 128.9, 128.8, 128.5, 128.4, 127.7, 121.0, 116.9,115.1, 70.4, 67.1, 63.3, 53.8; HRMS m/z: [M+H⁺] for C₂₆H₂₇N₂O₄, calcd,431.1971; found, 431.1974.

(E)-((5′-(benzyloxy)-2′-(2-nitrovinyl)-[1,1′-biphenyl]-4-yl)oxy)(tert-butyl)dimethylsilane(7m)

¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=13.7 Hz, 1H), 7.61 (d, J=8.3 Hz,1H), 7.49-7.33 (m, 6H), 7.17 (d, J=8.4 Hz, 2H), 7.02 (s, 2H), 6.95 (d,J=8.5 Hz, 2H), 5.15 (s, 2H), 1.04 (s, 9H), 0.30 (s, 6H); ¹³C NMR (100MHz, CDCl₃) δ 161.5, 156.2, 146.8, 138.5, 136.2, 135.8, 132.2, 131.0,129.6, 128.9, 128.5, 127.7, 121.1, 120.4, 116.8, 115.0, 70.4, 25.9,18.4,-4.1; HRMS (FAB) m/z: [M+Na⁺] for C₂₇H₃₁NO₄SiNa, calcd, 484.1914;found, 484.1936.

(E)-5-(5-(benzyloxy)-2-(2-nitrovinyl)phenyl)benzo[d][1,3]dioxole (7n)

¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=13.6 Hz, 1H), 7.59 (d, J=8.0 Hz,1H), 7.50-7.33 (m, 6H), 7.05-6.98 (m, 2H), 6.92-6.85 (m, 1H), 6.79 (s,1H), 6.71 (d, J=7.9 Hz, 1H), 6.03 (s, 2H), 5.17 (s, 2H); ¹³C NMR (100MHz, CDCl₃) δ 161.4, 148.0, 147.9, 146.5, 138.1, 136.1, 135.7, 132.9,129.5, 128.8, 128.4, 127.6, 123.6, 121.0, 116.7, 115.0, 109.9, 108.5,101.5, 70.3; HRMS (FAB) m/z: [M+H⁺] for C₂₂H₁₈NO₅, calcd, 376.1185;found, 376.1160.

(E)-3-(5-(benzyloxy)-2-(2-nitrovinyl)phenyl)pyridine (7o)

¹H NMR (400 MHz, CDCl₃) δ 8.70 (dd, J=4.8, 1.6 Hz, 1H), 8.59 (d, J=1.6Hz, 1H), 7.89 (d, J=13.5 Hz, 1H), 7.68-7.60 (m, 2H), 7.47-7.32 (m, 8H),7.12-7.06 (dd, J=8.7, 2.5 Hz, 1H), 7.00 (d, J=2.6 Hz, 1H), 5.15 (s, 2H);¹³C NMR (100 MHz, CDCl₃) δ 161.5, 149.9, 149.6, 142.8, 136.9, 136.8,136.3, 135.8, 134.8, 129.7, 128.8, 128.5, 127.6, 123.4, 121.1, 117.1,115.8, 70.4; HRMS (FAB) m/z: [M+Na⁺] for C₂₀H₁₇N₂O₃, 333.1239; found,333.1234.

(E)-4-(5-(benzyloxy)-2-(2-nitrovinyl)phenyl)pyridine (7p)

¹H NMR (500 MHz, CDCl3) δ 8.74 (dd, 2H, J=1.6, 4.4 Hz), 7.91 (d, 1H,J=13.6 Hz), 7.67 (d, 1H, J=8.8 Hz), 7.48 (d, 1H, J=13.4 Hz), 7.41 (m,5H), 7.25 (dd, 2H, J=1.6, 4.4 Hz), 7.11 (dd, 1H, J=2.6, 8.7 Hz), 7.01(d, 1H, J=2.5 Hz), 5.17 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 161.2,150.2, 147.0, 143.7, 136.7, 136.6, 135.8, 128.9, 127.6, 124.5, 120.7,116.8, 116.1, 70.6; ESI-HRMS m/z calculated for C₂₀H₁₇N₂O₃ [M+H]⁺333.1239, found 333.1249.

Example 8. General Procedure for Preparation of 8a-p from 7a-pN-(2-(5-(benzyloxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide (8a)

Nitrostyrene 7a (182 mg, 0.55 mmol) in THF (0.7 mL) was added dropwiseto a solution of Lithiumaluminium hydride (42 mg, 1.12 mmol) in THF (2mL) under organ atmosphere at RT. Upon completion (nearly immediately)the reaction was quenched by the addition of water (42 μL), 3M NaOH (42μL), and water (84 μL). The resulted mixture was filtered through a plugof celite, washed with DCM, and dried over K₂CO₃. Upon filtration themixture was concentrated to oil and used without further purification.Acetic anhydride (58 μL, 0.62 mmol) and triethylamine (93 μL, 0.67 mmol)were added to a solution of the crude amine in DCM (5.6 mL) under anorgan atmosphere at RT. After 3 h the reaction was quenched withsaturated aqueous ammonium chloride and extracted with DCM (3×10 mL);combined organic fractions were washed with saturated aqueoussodiumchloride, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (SiO₂; 3:1, Hex:EtOAc) toafford acetamide 8a (0.12 g, 0.35 mmol, 64%). ¹H NMR (400 MHz, CDCl₃) δ7.50-7.38 (m, 8H), 7.38-7.30 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.01-6.95(dd, J=8.4, 2.7 Hz, 1H), 6.93 (d, J=2.7 Hz, 1H), 5.71 (br s, NH), 5.08(s, 2H), 3.42-3.16 (q, J=7.0 Hz, 2H), 2.89-2.64 (t, J=7.2 Hz, 2H), 1.85(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.2, 157.2, 143.4, 141.4, 137.0,130.8, 129.1, 128.7, 128.6, 128.4, 128.0, 127.6, 127.2, 116.6, 114.2,70.1, 40.7, 31.9, 23.2; HRMS m/z: [M+K⁺] for C₂₃H₂₃NO₂K calcd, 384.1361;found, 384.1359.

N-(2-(5-(benzyloxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (8b)

¹H NMR (400 MHz, CDCl₃) δ 7.48-7.30 (m, 6H), 7.24-7.18 (d, J=8.4 Hz,1H), 7.12-7.04 (m, 2H), 7.04-6.92 (ddd, J=18.6, 8.2, 2.5 Hz, 2H), 6.85(d, J=2.7 Hz, 1H), 5.34 (br s, NH), 5.05 (s, 2H), 3.32-3.21 (q, J=6.4,5.9 Hz, 2H), 2.79-2.68 (t, J=7.1 Hz, 2H), 1.86 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 170.3, 157.3, 143.7, 142.2, 136.9, 131.0, 130.1, 123.0,128.8, 128.6, 128.2, 127.7, 125.0, 116.5, 116.4, 114.6, 114.4, 70.2,40.8, 32.0, 23.3; HRMS m/z: [M+H⁺] for C₂₃H₂₃FNO₂, calcd, 364.1713;found, 364.1705.

N-(2-(5-(benzyloxy)-4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (8c)

¹H NMR (400 MHz, CDCl₃) δ 7.44-7.31 (m, 6H), 7.27-7.22 (dd, J=8.4, 5.5Hz, 1H), 7.21-7.17 (d, J=8.4 Hz, 1H), 7.12-7.05 (m, 3H), 6.96-6.91 (dd,J=8.3, 3.0 Hz, 1H), 5.83 (br s, NH), 5.05 (s, 2H), 3.33-3.15 (q, J=6.7Hz, 2H), 2.78-2.66 (t, J=7.2 Hz, 2H), 1.87 (s, 3H); ¹³C NMR (100 MHz,CDCl₃) δ 170.5, 157.3, 142.4, 137.0, 130.9, 130.8, 130.7, 128.7, 128.7,128.2, 127.7, 116.8, 115.5, 115.3, 114.3, 70.2, 40.8, 32.0, 23.1; HRMSm/z: [M+Na⁺] for C₂₃H₂₂FNO₂Na, calcd, 386.1527; found, 386.1529.

N-(2-(5-(benzyloxy)-2′-chloro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (8d)

¹H NMR (500 MHz, CDCl₃) δ 7.52-7.45 (m, 1H), 7.45-7.40 (m, 2H),7.40-7.35 (m, 3H), 7.35-7.29 (m, 3H), 7.25-7.21 (m, 1H), 7.05-6.95 (dd,J=8.5, 2.8 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 5.93 (d, J=5.4 Hz, 1H), 5.05(s, 2H), 3.36-3.19 (ddq, J=19.3, 13.0, 6.1 Hz, 2H), 2.67-2.49 (m, 2H),1.93 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 175.7, 171.0, 157.1, 140.4,139.8, 136.9, 133.1, 131.3, 130.4, 129.6, 129.0, 128.6, 128.0, 127.6,126.8, 116.4, 114.9, 70.1, 40.3, 31.8, 22.9; HRMS m/z: [M+H⁺] forC₂₃H₂₃ClNO₂, calcd, 380.1417; found, 380.1415.

N-(2-(5-(benzyloxy)-3′-chloro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (8e)

¹H NMR (500 MHz, CDCl₃) δ 7.47-7.28 (m, 8H), 7.25-7.17 (m, 2H),6.99-6.92 (dd, J=8.5, 2.7 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 5.46 (br s,NH), 5.06 (s, 2H), 3.34-3.25 (m, 2H), 2.83-2.68 (t, J=7.3 Hz, 2H), 2.03(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 171.6, 157.5, 143.2, 142.1, 136.9,134.3, 131.1, 129.9 129.3, 128.8, 128.3, 127.7, 127.6, 127.5, 116.7,114.8, 70.3, 46.1, 41.3, 31.7, 22.5, 8.8; HRMS m/z: [M+H⁺] forC₂₃H₂₃ClNO₂, calcd, 380.1412; found, 380.1414.

N-(2-(5-(benzyloxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(8f)

¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J=7.7 Hz, 1H), 7.59-7.54 (m, 2H),7.55-7.49 (t, J=7.3 Hz, 1H), 7.47-7.32 (m, 5H), 7.24 (d, J=8.5 Hz, 1H),7.01-6.96 (dd, J=8.5, 2.7 Hz, 1H), 6.87 (d, J=2.7 Hz, 1H), 5.90 (br s,NH), 5.06 (s, 2H), 3.34-3.23 (q, J=6.9 Hz, 2H), 2.79-2.68 (t, J=7.3 Hz,2H), 1.99 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 157.4, 142.2,141.9, 136.9, 132.6, 131.1, 129.0, 128.8, 128.5, 128.2, 127.7, 124.2,116.7, 114.8, 70.3, 40.8 31.9, 23.0; HRMS m/z: [M+H⁺] for C₂₄H₂₃F₃NO₂,calcd, 414.1676; found, 414.1681.

N-(2-(5-(benzyloxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(8g)

¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J=8.1 Hz, 2H), 7.46-7.23 (m, 8H),6.99-6.94 (dd, J=8.5, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 6.03 (t,J=5.5 Hz, 1H), 5.06 (s, 2H), 3.33-3.19 (dd, J=14.3, 6.4 Hz, 2H),2.76-2.68 (dd, J=8.3, 6.6 Hz, 2H), 1.85 (s, 3H); ¹³C NMR (100 MHz,CDCl₃) δ 170.3, 157.1, 145.1, 141.8, 136.8, 130.9, 129.5, 129.1, 128.6,128.6, 127.5, 125.6, 125.2, 125.2, 122.9, 116.4, 114.6, 70.1, 40.6,31.9; HRMS m/z: [M+Na⁺] for C₂₄H₂₂F₃NO₂Na, calcd, 436.1495; found,436.1489.

N-(2-(5-(benzyloxy)-2′-(methylthio)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(8h)

¹H NMR (400 MHz, CDCl₃) δ 7.48-7.30 (m, 7H), 7.28-7.18 (m, 2H), 7.14 (s,1H), 7.03-6.98 (ddd, J=8.5, 2.8, 1.0 Hz, 1H), 6.87-6.83 (m, 1H), 5.63(br s, NH), 5.05 (s, 2H), 3.43-3.16 (ddt, J=42.5, 13.3, 6.6 Hz, 2H),2.66-2.52 (t, J=6.7 Hz, 2H), 2.39 (d, J=1.0 Hz, 3H), 1.84 (d, J=1.0 Hz,3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.3, 157.3, 141.1, 139.1, 137.6,137.0, 130.6, 129.8, 129.4, 128.7, 128.4, 128.1, 127.7, 124.5, 124.0,116.5, 115.2, 70.2, 40.1, 31.7, 23.3, 15.2; HRMS m/z: [M+Na⁺] forC₂₄H₂₅NO₂SNa, calcd, 414.1504; found, 414.1509.

N-(2-(5-(benzyloxy)-2′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (8i)

¹H NMR (400 MHz, CDCl₃) δ 7.47-7.30 (m, 5H), 7.22 (d, J=8.5 Hz, 1H),7.17-7.13 (dd, J=7.4, 1.9 Hz, 1H), 7.07-6.95 (m, 4H), 6.85 (d, J=2.7 Hz,1H), 5.51 (br s, NH), 5.07 (s, 2H), 3.77 (s, 3H), 3.44-3.18 (m, 2H),2.68-2.56 (td, J=6.8, 3.7 Hz, 2H), 1.86 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 170.0, 157.2, 156.4, 139.9, 137.1, 131.2, 130.1, 129.2, 128.7,128.1, 127.8, 120.9, 116.8, 114.4, 111.2, 70.1, 55.8, 40.4, 31.9, 23.5;HRMS m/z: [M+H⁺] for C₂₄H₂₆NO₃, calcd, 376.1913; found, 376.1902.

N-(2-(5-(benzyloxy)-3′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (8j)

¹H NMR (400 MHz, CDCl₃) δ 7.48-7.36 (m, 4H), 7.36-7.30 (m, 3H), 7.21 (d,J=8.4 Hz, 1H), 6.98-6.92 (m, 1H), 6.92-6.82 (m, 3H), 5.49 (br s, NH),5.06 (s, 2H), 3.85 (s, 3H), 3.34-3.22 (q, J=6.6, 6.2 Hz, 2H), 2.85-2.68(t, J=7.2 Hz, 2H), 1.85 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.1,159.5, 157.2, 143.3, 142.9, 137.0, 130.8, 129.5, 128.7, 128.1, 128.1,127.7, 121.6, 116.5, 114.9, 114.3, 112.7, 70.17, 55.4, 40.8, 32.0, 23.3;HRMS m/z: [M+H⁺] for C₂₄H₂₅NO₃Na, calcd, 398.1732; found, 398.1725.

N-(2-(5-(benzyloxy)-3′-methyl-[1,1′-biphenyl]-2-yl)ethyl)acetamide (8k)

¹H NMR (400 MHz, CDCl₃) δ 7.45 (m, 3H), 7.40 (m, 3H), 7.37-7.30 (q,J=7.7, 7.1 Hz, 1H), 7.21 (d, J=1.4 Hz, 1H), 7.15-7.10 (m, 2H), 6.96 (d,J=8.1 Hz, 1H), 6.90 (s, 1H), 5.51 (br s, NH), 5.08 (s, 2H), 3.34-3.24(q, J=6.5 Hz, 2H), 2.83-2.71 (t, J=7.0 Hz, 2H), 2.41 (s, 3H), 1.84 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.0, 157.2, 143.5, 141.4, 138.0,137.0, 130.7, 129.9, 128.7, 128.7, 128.3, 128.1, 128.0, 127.6, 126.2,116.5, 114.2, 70.1, 40.8, 31.9, 23.3, 21.6; ESI-HRMS m/z calculated forC₂₄H₂₅NO₂Na [M+Na]⁺382.1777, found 382.1770.

N-(2-(5-(benzyloxy)-3′-(morpholinomethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(8l)

¹H NMR (400 MHz, CDCl₃) δ 7.47-7.30 (m, 7H), 7.28 (s, 1H), 7.24-7.18 (m,2H), 6.98-6.93 (dd, J=8.4, 2.8 Hz, 1H), 6.89 (d, J=2.7 Hz, 1H), 5.40 (s,1H), 5.05 (s, 2H), 3.75-3.69 (t, J=4.7 Hz, 4H), 3.55 (s, 2H), 3.36-3.22(q, J=6.9 Hz, 2H), 2.80-2.68 (t, J=7.1 Hz, 2H), 2.47 (m, 4H), 1.85 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.0, 157.3, 143.4, 141.5, 138.0,137.1, 130.9, 123.0, 128.7, 128.7, 128.4, 128.2, 128.2, 128.0, 127.7,116.8, 114.1, 70.2, 67.1, 63.5, 53.8, 40.6, 32.1, 23.4; HRMS m/z: [M+H⁺]for C₂₈H₃₃N₂O₃, calcd, 445.2491; found, 445.2494.

N-(2-(5-(benzyloxy)-4′-((tert-butyldimethylsilyl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(8m)

¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J=7.5 Hz, 3H), 7.42-7.36 (dt, J=10.5,5.7 Hz, 3H), 7.36-7.31 (m, 1H), 7.21-7.14 (m, 3H), 6.94-6.86 (m, 2H),5.08 (s, 2H), 3.34-3.23 (q, J=6.7 Hz, 2H), 2.75 (t, J=7.1 Hz, 2H), 1.74(s, 3H), 1.97 (s, 9H), 0.25 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 169.9,157.3, 155.0, 143.3, 137.2, 134.5, 130.8, 130.2, 128.7, 128.1, 127.7,120.0, 116.8, 114.0, 70.2, 53.6, 40.7, 32.1, 25.8, 23.4, 18.4, −4.2;HRMS (FAB) m/z: [M+Na⁺] for C₂₉H₃₇NO₃SiNa, calcd, 498.2440; found,498.2447.

N-(2-(benzo[d][1,3]dioxol-5-yl)-4-(benzyloxy)phenethyl)acetamide (8n)

¹H NMR (400 MHz, CDCl₃) δ 7.49-7.36 (m, 5H), 7.34 (d, J=4.4 Hz, 1H),7.20 (d, J=8.3 Hz, 1H), 6.96-6.89 (dd, J=8.4, 2.8 Hz, 1H), 6.90-6.84 (m,2H), 6.81-6.73 (m, 1H), 6.00 (s, 2H), 5.69-5.60 (t, J=5.8 Hz, 1H), 5.06(s, 2H), 3.42-3.16 (m, 2H), 2.93-2.68 (t, J=7.3 Hz, 2H), 1.87 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 170.4, 157.2, 147.5, 146.8, 143.0, 137.0,135.2, 130.8, 129.3, 128.8, 128.1, 127.6, 123.2, 122.4, 116.7, 114.1,109.7, 108.3, 101.2, 70.1, 40.7, 31.9, 23.2; HRMS (FAB) m/z: [M+Na⁺] forC₂₄H₂₃NO₄Na, 412.1519; found, 412.1524.

N-(4-(benzyloxy)-2-(pyridin-3-yl)phenethyl)acetamide (8o)

¹H NMR (400 MHz, CDCl₃) δ 8.69-8.52 (dd, J=18.2, 4.0 Hz, 2H), 7.71-7.63(dt, J=7.8, 2.0 Hz, 1H), 7.49-7.31 (m, 7H), 7.06-6.97 (dd, J=8.5, 2.8Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 5.06 (s, 2H), 3.36-3.20 (q, J=6.5 Hz,2H), 2.78-2.67 (dd, J=8.1, 6.6 Hz, 2H), 1.90 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 170.1, 157.5, 149.6, 148.5, 139.5, 136.9, 131.2, 129.0, 128.8,128.3, 127.7, 123.5, 116.9, 115.0, 70.3, 40.7, 32.2, 23.5; HRMS (FAB)m/z: [M+H⁺] for C₂₂H₂₃N₂O₂, calcd, 347.1759; found, 347.1754.

N-(4-(benzyloxy)-2-(pyridin-4-yl)phenethyl)acetamide (8p)

¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J=5.1 Hz, 2H), 7.46-7.39 (m, 5H),7.36 (s, 1H), 7.30 (s, 2H), 7.06-7.01 (m, 1H), 6.84 (d, J=2.7 Hz, 1H),5.94 (d, J=4.8 Hz, 1H), 5.09 (s, 2H), 3.35-3.23 (dd, J=14.5, 6.4 Hz,2H), 2.74 (t, J=7.5 Hz, 2H), 1.90 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ171.4, 158.1, 156.3, 137.2, 132.3, 132.2, 130.8, 128.7, 128.5, 129.7,127.5, 117.9, 106.2, 103.0, 69.9, 41.1, 29.7, 29.6, 23.1; HRMS (FAB)m/z: [M+Na⁺] for C₂₂H₂₂N₂O₂Na, calcd, 369.1579; found, 369.1573.

Example 9. General Hydrogenolysis Procedure for Compounds 8a-pN-(2-(5-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (9a)

Palladium on carbon (10%, 5 mg) was added to 8a (120 mg, 0.35 mmol) indegassed MeOH (3.5 mL) and the solution was placed under an atmosphereof H₂. After 12 h, the solution was diluted with DCM and filteredthrough Celite. The eluent was concentrated to afford a yellow solid,which was purified by column chromatography (SiO₂, 100:5, DCM:MeOH) toafford phenol 9a (64 mg, 0.25 mmol, 79%) as a pale yellow amorphoussolid. ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.14 (m, 5H), 7.11-7.05 (m, 1H),6.90 (d, J=8.3 Hz, 1H), 6.64 (d, J=8.3 Hz, 1H), 6.59 (d, J=2.5 Hz, 1H),5.61 (t, J=5.5 Hz, 1H), 3.12-3.02 (m, 2H), 2.55 (t, J=7.1 Hz, 2H), 1.66(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.2, 155.2, 143.4, 141.6, 130.8,129.1, 128.4, 127.2, 127.2, 117.4, 115.0, 41.1, 31.8, 23.2; HRMS m/z:[M+Na⁺] for C₁₆H₁₇NO₂Na, calcd, 278.1151; found, 278.1155.

N-(2-(3′-fluoro-5-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (9b)

¹H NMR (500 MHz, MeOD) δ 7.88 (s, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.16-6.99(m, 4H), 6.77 (d, J=8.1 Hz, 1H), 6.62 (d, J=2.6 Hz, 1H), 3.15 (t, J=6.6Hz, 2H), 2.66 (t, J=7.4 Hz, 2H), 1.80 (s, 3H); ¹³C NMR (125 MHz, MeOD) δ173.1, 164.8, 162.9, 156.7, 145.5, 143.3, 132.0, 131.0, 128.3, 126.1,117.6, 115.9, 114.7, 41.8, 32.8, 22.5; HRMS m/z: [M+Na⁺] forC₁₆H₁₆FNO₂Na, calcd, 296.1063; found, 296.1059.

N-(2-(4′-fluoro-5-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (9c)

¹H NMR (400 MHz, MeOD) δ 7.26-7.20 (m, 2H), 7.11-7.03 (m, 3H), 6.71 (dd,J=8.3, 2.5 Hz, 1H), 6.56 (d, J=2.5 Hz, 1H), 3.07 (t, J=7.6 Hz, 2H), 2.60(t, J=7.6 Hz, 2H), 1.78 (s, 3H); ¹³C NMR (100 MHz, MeOD) δ 173.0, 156.7,143.5, 139.2, 131.9, 131.9, 131.8, 128.5, 117.8, 116.0, 115.8, 115.7,41.8, 32.9, 22.5; HRMS m/z: [M+Na⁺] for C₁₆H₁₆FNO₂Na, calcd, 296.1063;found, 296.1065.

N-(2-(2′-chloro-5-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (9d)

¹H NMR (400 MHz, CDCl₃) δ 8.37 (br s, OH), 7.45-7.39 (m, 1H), 7.32-7.24(m, 2H), 7.21-7.15 (m, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.85 (dd, J=8.3, 2.5Hz, 1H), 6.68 (d, J=2.6 Hz, 1H), 5.62 (s, 1H), 3.40-3.14 (m, 2H),2.63-2.44 (dd, J=7.1, 5.1 Hz, 2H), 1.86 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 171.1, 155.1, 140.5, 140.0, 133.2, 131.4, 130.5, 129.7, 129.0,127.7, 126.9, 117.3, 115.7, 40.5, 31.8, 23.3; HRMS m/z: [M+H⁺] forC₁₆H₁₇ClNO₂, 290.0948; found, 290.0941.

N-(2-(3′-chloro-5-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (9e)

¹H NMR (500 MHz, CDCl₃) δ 7.40-7.09 (m, 5H), 6.83-6.76 (dq, J=8.1, 4.9,3.8 Hz, 1H), 6.76-6.67 (dd, J=18.3, 2.7 Hz, 1H), 3.34-3.23 (p, J=6.6 Hz,2H), 2.77-2.64 (dt, J=14.3, 7.2 Hz, 2H), 1.76 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 170.8, 154.9, 143.6, 141.6, 131.0, 130.9, 129.7, 129.2, 128.5,127.5, 117.4, 115.5, 115.0, 41.0, 32.0, 23.4; HRMS m/z: [M+Na⁺] forC₁₆H₁₆ClNO₂Na, calcd, 312.0762; found, 312.0788.

N-(2-(5-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(9f)

¹H NMR (400 MHz, CDCl₃) δ 7.64-7.39 (m, 4H), 7.07 (s, 1H), 6.82 (s, 1H),6.73 (s, 1H), 6.00 (s, 1H), 3.34-3.18 (q, J=6.8 Hz, 2H), 2.66 (t, J=7.0Hz, 2H), 1.87 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 155.4, 142.4,141.8, 132.6, 131.0, 130.8, 128.9, 126.9, 125.8, 125.8, 124.0, 117.3,115.6, 60.7, 41.0, 21.2; HRMS m/z: [M+Na⁺] for C₁₇H₁₆F₃NO₂Na, calcd,346.1031; found, 346.1040.

N-(2-(5-hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(9g)

¹H NMR (400 MHz, CDCl3) δ 7.54 (d, 2H, J=8.0 Hz), 7.31 (d, 2H, J=8.0Hz), 7.03 (d, 1H, J=8.3 Hz), 6.72 (dd, 1H, J=2.5, 8.3 Hz), 6.59 (d, 1H,J=2.5 Hz), 4.09 (br s, 2H), 3.10 (t, J=7.5 Hz, 2H), 2.56 (t, 2H, J=7.5Hz), 1.76 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.5, 155.1, 146.3,141.7, 130.8, 129.5, 127.1, 125.1 (q, J=4.2 Hz), 116.9, 116.5, 115.3,45.6, 40.6, 23.0; HRMS m/z: [M+H⁺] for C₁₇H₁₆F₃NO₂Na, calcd, 346.1031;found, 346.1025.

N-(2-(5-hydroxy-2′-(methylthio)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(9h)

¹H NMR (500 MHz, CDCl₃) δ 7.40-7.34 (m, 1H), 7.25-7.14 (m, 3H),7.12-7.07 (m, 1H), 6.86-6.82 (dd, J=8.4, 2.7 Hz, 1H), 6.68 (d, J=2.7 Hz,1H), 5.51 (br s, NH), 3.42-3.16 (m, 2H), 2.55 (t, J=6.8 Hz, 2H), 2.37(s, 3H), 1.85 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.5, 154.5, 141.2,139.1, 137.6, 130.7, 123.0, 128.8, 128.5, 124.6, 124.0, 117.3, 115.6,40.2, 31.6, 23.4, 15.2; HRMS m/z: [M+Na⁺] for C₁₇H₁₉NO₂SNa, calcd,324.1034; found, 324.1035.

N-(2-(5-hydroxy-2′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (9i)

¹H NMR (400 MHz, CDCl₃) δ 7.52 (br s, OH), 7.41-7.31 (m, 1H), 7.14-7.07(dd, J=8.4, 6.4 Hz, 1H), 7.05-6.94 (m, 3H), 6.83-6.76 (dd, J=8.3, 2.7Hz, 1H), 6.70 (d, J=2.7 Hz, 1H), 5.55 (s, 1H), 3.76 (s, 3H), 3.41-3.17(ddt, J=34.4, 13.1, 6.5 Hz, 2H), 2.57 (t, J=6.9 Hz, 2H), 1.85 (s, 3H);¹³C NMR (125 MHz, CDCl₃) δ 171.0, 156.4, 155.1, 139.9, 131.3, 130.5,130.1, 129.1, 128.5, 121.0, 117.7, 115.2, 111.4, 55.9, 40.7, 31.7, 23.3;HRMS m/z: [M+Na⁺] for C₁₇H₁₉NO₃Na, calcd, 308.1263; found, 308.1264.

N-(2-(5-hydroxy-3′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (9j)

¹H NMR (400 MHz, CDCl₃) δ 7.83 (br s, OH), 7.30-7.24 (m, 1H), 7.06 (d,J=8.2 Hz, 1H), 6.90-6.70 (m, 5H), 5.59 (t, J=5.7 Hz, 1H), 3.79 (s, 3H),3.33-3.19 (q, J=6.9 Hz, 2H), 2.69 (t, J=7.1 Hz, 2H), 1.85 (s, 3H); ¹³CNMR (100 MHz, CDCl₃) δ 171.1, 159.4, 155.1, 143.3, 143.0, 130.9, 129.5,127.3, 121.7, 117.2, 115.1, 115.0, 112.6, 55.4, 41.1, 31.8, 23.3; HRMSm/z: [M+H⁺] for C₁₇H₂₀NO₃, calcd, 286.1443; found, 286.1436.

N-(2-(5-hydroxy-3′-methyl-[1,1′-biphenyl]-2-yl)ethyl)acetamide (9k)

¹H NMR (400 MHz, CDCl₃) δ 7.50 (br s, OH), 7.30-7.24 (m, 1H), 7.15 (d,J=7.6 Hz, 1H), 7.09-7.03 (m, 3H), 6.80 (d, J=7.6 Hz, 1H), 6.73 (s, 1H),5.53 (br s, NH), 3.31-3.21 (q, J=6.7 Hz, 2H), 2.71 (t, J=7.0 Hz, 2H),2.37 (s, 3H), 1.85 (s, 3H); ¹³C NMR (1001 MHz, CDCl₃) δ 170.9, 155.0,143.6, 141.6, 138.1, 130.8, 1230.0, 128.3, 128.0, 127.4, 126.3, 117.4,114.9, 41.1, 31.8, 23.3, 21.7; HRMS m/z: [M+Na⁺] for C₁₇H₁₉NO₂Na, calcd,292.1308; found, 292.1314.

N-(2-(5-hydroxy-3′-(morpholinomethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(9l)

¹H NMR (500 MHz, CDCl₃) δ 7.36-7.23 (m, 4H), 7.16 (d, J=7.2 Hz, 1H),7.07 (d, J=8.2 Hz, 1H), 6.74-6.69 (dd, J=8.2, 2.7 Hz, 1H), 6.62 (d,J=2.6 Hz, 1H), 5.50 (br s, NH), 3.74 (m, 4H), 3.53 (s, 3H), 3.29-3.20(q, J=6.7 Hz, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.49 (t, J=4.8 Hz, 4H), 1.87(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.5, 155.0, 143.4, 141.7, 130.9,130.2, 128.4, 128.2, 117.5, 115.0, 66.9, 63.4, 53.8, 40.8, 32.0, 23.4;HRMS m/z: [M+H⁺] for C₂₁H₂₇N₂O₃, calcd, 355.2022; found, 355.2024.

N-(2-(4′-((tert-butyldimethylsilyl)oxy)-5-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(9m)

¹H NMR (500 MHz, CDCl₃) δ 7.16-7.10 (d, J=6.7 Hz, 2H), 7.10-7.06 (d,J=8.2 Hz, 1H), 7.00 (br s, OH), 6.91-6.84 (d, J=8.4 Hz, 2H), 6.79-6.72(m, 2H), 5.38 (s, 1H), 3.34-3.21 (q, J=6.6 Hz, 2H), 2.78-2.64 (t, J=6.9Hz, 2H), 1.93-1.81 (s, 3H), 1.00 (s, 9H), 0.24 (s, 6H); ¹³C NMR (125MHz, CDCl₃) δ 170.7, 155.0, 154.9, 143.3, 134.6, 130.9, 130.3, 127.8,120.0, 117.5, 114.7, 41.0, 32.0, 26.0, 23.4, 18.4, −4.1; HRMS (FAB) m/z:[M+Na⁺] for C₂₂H₃₁NO₃SiNa, calcd, 408.1965; found, 408.1960.

N-(2-(benzo[d][1,3]dioxol-5-yl)-4-hydroxyphenethyl)acetamide (9n)

¹H NMR (500 MHz, CDCl₃) δ 8.00 (br s, OH), 7.08-6.98 (d, J=8.3 Hz, 1H),6.81-6.73 (m, 2H), 6.73-6.68 (m, 2H), 6.68-6.64 (dd, J=7.9, 1.7 Hz, 1H),5.97-5.92 (s, 2H), 5.70-5.63 (t, J=5.7 Hz, 1H), 3.29-3.21 (td, J=7.1,5.6 Hz, 2H), 2.75-2.63 (t, J=7.2 Hz, 2H), 1.89-1.81 (s, 3H); ¹³C NMR(125 MHz, CDCl₃) δ 171.1, 155.1, 147.5, 146.8, 143.0, 135.4, 130.8,127.4, 122.4, 117.5, 114.9, 109.8, 108.3, 101.2, 41.1, 31.9, 23.3; HRMS(FAB) m/z: [M+Na⁺] for C₁₇H₁₇NO₄Na, calcd, 322.1050; found, 322.1022.

N-(4-hydroxy-2-(pyridin-3-yl)phenethyl)acetamide (9o)

¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 2H), 7.72 (d, J=7.9 Hz, 1H),7.42-7.34 (dd, J=8.0, 4.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.90-6.84(dd, J=8.3, 2.7 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H), 5.82 (t, J=5.9 Hz, 2H),3.33-3.19 (q, J=6.8 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 1.85 (s, 3H); ¹³CNMR (100 MHz, CDCl₃) δ 170.7, 156.1, 149.1, 147.7, 138.8, 138.0, 131.4,127.3, 123.7, 117.5, 116.4, 100.2, 40.9, 32.0, 23.4; HRMS (FAB) m/z:[M+H⁺] for C₁₅H₁₇N₂O₂, calcd, 257.1290; found, 257.1297.

N-(4-hydroxy-2-(pyridin-4-yl)phenethyl)acetamide (9p)

¹H NMR (400 MHz, CDCl₃) δ 8.69-8.60 (m, 2H), 7.25 (d, J=1.5 Hz, 2H),7.17 (d, J=8.4 Hz, 1H), 6.90-6.83 (dd, J=8.4, 2.7 Hz, 1H), 6.70 (d,J=2.7 Hz, 1H), 6.02 (br s, OH), 5.47 (s, 1H), 3.33-3.24 (q, J=7.0 Hz,2H), 2.71 (t, J=7.4 Hz, 2H), 1.90 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ173.0, 157.1, 152.8, 149.7, 149.6, 141.3, 132.4, 128.0, 126.2, 117.2,117.1, 116.9, 41.8, 32.8, 22.5; HRMS (FAB) m/z: [M+Na⁺] forC₁₅H₁₆N₂O₂Na, calcd, 279.1104; found, 279.1109.

Example 10. General Procedure for Activated Noviose Carbamate Couplingand Followed by Methanolysis of Compounds 9a-p

Borontrifluoride etherate (6.2 μL, 0.05 mmol) was added to 9a-p (0.25mmol) and activated noviose (0.2 mmol) in 2.5 mL anhydrous DCM. Afterstirring at RT for 2 h, triethylamine (150 μL) was added and the solventwas concentrated. The residue was partially purified via columnchromatography (SiO₂, 100:8 DCM:acetone) to give noviose coupled productas a colorless foam, which was used directly for next step.Triethylamine (0.22 mL, 10%) was added to the cyclic carbonate (100 mg,0.22 mmol) in MeOH (2.2 mL). After 12 h, the solvent was concentratedand the residue was purified via column chromatography (SiO₂, 10:1,DCM:Acetone) to afford inseparable diastereomers 11a-p (see followingexperimental section for diastereoselectivities) as a colorlessamorphous solids.

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11a)

Colorless amorphous solid (63% yield over 2 steps); ¹H NMR (500 MHz,CDCl₃) δ 7.41-7.28 (m, 3H), 7.28-7.18 (dt, J=5.9, 3.2 Hz, 2H), 7.13 (m,1H), 6.97 (m, 1H), 6.92-6.78 (dd, J=7.6, 2.7 Hz, 1H), 5.55-5.47 (dd,J=7.7, 2.7 Hz, 1H), 5.39 (m, 1H), 4.14 (m, 2H), 3.58-3.46 (m, 3H),3.34-3.15 (m, 4H), 3.03 (d, J=5.5 Hz, 1H), 2.77-2.65 (m, 2H), 1.84-1.76(m, 3H), 1.31 (d, J=4.9 Hz, 3H), 1.21-1.10 (m, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 170.3, 155.4, 143.5, 141.4, 130.8, 129.5, 129.2, 128.5, 127.4,118.2, 115.2, 98.1, 84.5, 78.4, 71.5, 68.8, 62.0, 40.8, 32.1, 29.2,23.4, 23.1; HRMS m/z: [M+H⁺] for C₂₄H₃₂NO₆, calcd, 430.2224; found,430.2227.

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11b)

Colorless amorphous solid (51% yield over 2 steps); ¹H NMR (500 MHz,CDCl3) δ 7.39 (dd, 1H, J=7.9, 13.9 Hz), 7.22 (d, 1H, J=8.5 Hz), 7.07(dd, 2H, J=7.5, 10.5 Hz), 7.02 (dd, 1H, J=2.8, 8.4 Hz), 6.99 (m, 1H),6.91 (d, 1H, J=2.7 Hz), 5.34 (d, 1H, J=1.3 Hz), 5.28 (s, 1H), 4.20 (d,1H, J=2.2 Hz), 3.80 (m, 1H), 3.63 (s, 3H), 3.30 (d, 1H), 3.28 (m, 2H),2.75 (t, 2H, J=7.2 Hz), 2.63 (m, 2H, J=15.9 Hz), 1.87 (s, 3H), 1.41 (s,3H), 1.28 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 169.9, 163.5-161.6 (d,J=251 Hz) 155.0, 143.2 (d, J=7.8 Hz), 142.1 (d, J=1.8 Hz), 130.9, 130.1,130.0 (d, J=8.8 Hz), 124.8 (d, J=2.8 Hz), 118.0, 116.0 (d, J=8.8 Hz),115.4, 114.3 (d, J=21.6 Hz), 93.8, 84.2, 76.0, 71.3, 71.1, 62.0, 40.4,32.0, 28.6, 23.3, 18.5; HRMS m/z: [M+H⁺] for C₂₄H₃₁FNO₆, calcd,448.2180; found, 448.2174. This material was determined to be 95.6% pure(retention time=6.401) by HPLC (Phenomenex Luna C-18, 5 μm, 10×250 mmcolumn eluting with 30% CH₃CN, 70% H₂O, flow rate 5.0 mL/min).

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11c)

Colorless amorphous solid (57% yield over 2 steps); ¹H NMR (500 MHz,CDCl3) δ 7.25 (dd, 2H, J=5.4, 8.6 Hz), 7.18 (d, 1H, J=8.5 Hz), 7.10 (t,2H, J=8.7 Hz), 7.01 (dd, 1H, J=2.7, 8.5 Hz), 6.87 (d, 1H, J=2.7 Hz),5.54 (d, 1H, J=2.2 Hz), 5.37 (t, 1H, J=5.2 Hz), 4.20 (dd, 1H, J=3.3, 9.1Hz), 4.15 (m, 1H), 3.59 (s, 3H), 3.33 (d, 1H, J=9.1 Hz), 3.26 (q, 2H,J=6.9 Hz), 2.97 (s, 1H), 2.81 (s, 1H), 2.72 (t, 2H, J=7.3), 1.87 (s,3H), 1.36 (s, 3H), 1.22 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.2,163.2-161.3 (d, J=250 Hz), 155.3, 142.3, 137.2 (d, J=3.2 Hz), 130.8,130.8, 130.7, 129.5, 118.1, 115.4, 115.3, 115.3, 97.9, 84.4, 78.3, 71.4,68.7, 62.0, 40.6, 32.1, 29.1, 23.4, 23.1; HRMS m/z: [M+Na⁺] forC₂₄H₃₀FNO₆, calcd, 470.1955; found, 470.1958.

N-(2-(2′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11d)

Colorless amorphous solid (62% yield over 2 steps); ¹H NMR (500 MHz,CDCl3) δ 7.46 (m, 1H), 7.31 (m, 2H), 7.21 (m, 2H), 7.03 (m, 1H), 6.86(dd, 1H, J=2.7, 13.2 Hz), 5.55 (m, 1H), 5.42 (s, 1H), 4.20 (dt, 1H,J=3.0, 9.1 Hz), 4.14 (m, 1H), 3.59 (s, 3H), 3.33 (dd, 1H, J=2.5, 9.1Hz), 3.26 (ddt, 2H, J=4.8, 6.8, 9.3 Hz), 3.11 (s, 1H), 2.93 (s, 1H),2.58 (tq, 2H, J=7.1, 14.2 Hz), 1.86 (s, 3H), 1.35 (d, 3H, J=2.4 Hz),1.20 (t, 3H, J=5.8 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 170.2, 155.2, 140.6,140.5, 139.8, 133.4, 131.4, 130.5, 129.8, 126.9, 118.1, 117.9, 116.05,97.9, 84.5, 78.4, 71.5, 71.4, 68.7, 62.1, 62.0, 40.2, 40.2, 32.1, 32.1,29.3, 29.2, 23.5, 23.1, 23.0; HRMS m/z: [M+Na⁺] for C₂₄H₃₀ClNO₆Na,486.1659; found, 486.1652.

N-(2-(3′-chloro-5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11e)

Colorless amorphous solid (55% yield over 2 steps); ¹H NMR (500 MHz,CDCl3) δ 7.35 (m, 2H), 7.28 (m, 1H), 7.18 (m, 2H), 7.03 (dd, 1H, J=2.7,8.5 Hz), 6.87 (d, 1H, J=2.7 Hz), 5.55 (t, 1H, J=2.5 Hz), 5.34 (m, 1H),4.21 (dd, 1H, J=3.1, 9.1 Hz), 4.16 (m, 1H), 3.60 (s, 3H), 3.34 (dd, 1H,J=1.9, 9.1 Hz), 3.28 (m, 2H), 2.75 (dt, 4H, J=7.3, 14.5 Hz), 1.88 (s,3H), 1.37 (s, 3H), 1.22 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.1,155.4, 143.5, 142.0, 134.3, 131.0, 130.9, 129.8, 129.4, 128.5, 127.6,127.4, 118.2, 115.7, 97.9, 84.6, 78.4, 71.5, 68.7, 62.1, 40.8, 32.1,29.2, 23.6, 23.1; HRMS m/z: [M+Na⁺] for C₂₄H₃₀ClNO₆Na, calcd, 486.1659;found, 486.1642.

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11f)

Colorless amorphous solid (52% yield over 2 steps); ¹H NMR (500 MHz,CDCl3) δ 7.64 (d, 1H, J=7.7 Hz), 7.55 (t, 2H, J=7.6 Hz), 7.49 (m, 1H),7.23 (d, 1H, J=8.5 Hz), 7.06 (dd, 1H, J=2.7, 8.4 Hz), 6.89 (d, 1H, J=2.7Hz), 5.56 (d, 1H, J=2.2 Hz), 5.31 (s, 1H), 4.19 (m, 2H), 3.60 (s, 3H),3.34 (d, 1H, J=9.1 Hz), 3.29 (dd, 2H, J=7.0, 13.3 Hz), 2.72 (t, 2H,J=7.3 Hz), 2.69 (s, 1H), 2.64 (s, 1H), 1.87 (s, 3H), 1.37 (s, 3H), 1.22(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.1, 155.4, 142.1, 141.9, 132.6,131.0, 130.7 (q, J=31.5 Hz), 129.4, 129.0, 125.9 (q, J=3.6, 7.2 Hz),125.3, 124.2 (q, J=3.6, 7.2 Hz), 123.1, 118.0, 115.8, 97.9, 84.4, 77.4,71.4, 68.7, 62.0, 40.6, 32.1, 29.8, 29.2, 23.4, 23.0; HRMS m/z: [M+Na⁺]for C₂₅H₃₀F₃NO₆Na, 520.1923; found, 520.1932. This material wasdetermined to be 97.2% pure (retention time=7.631) by HPLC (PhenomenexLuna C-18, 5 μm, 10×250 mm column eluting with 30% CH₃CN, 70% H₂O, flowrate 5.0 mL/min).

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11g)

Colorless amorphous solid (49% yield over 2 steps); ¹H NMR (400 MHz,CDCl₃) δ 7.70 (d, J=7.6 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 7.24 (d, J=8.4Hz, 1H), 7.09-7.03 (dd, J=8.6, 2.7 Hz, 1H), 6.90 (d, J=2.7 Hz, 1H), 5.55(d, J=2.3 Hz, 1H), 5.33 (m, 1H), 4.26-4.11 (m, 2H), 3.60 (s, 3H),3.36-3.25 (m, 3H), 2.74 (t, J=7.4 Hz, 2H), 2.56 (br s, 20H), 1.88 (s,3H), 1.37 (s, 3H), 1.22 (s, 3H); ¹³C NMR (125 MHz, MeOD) δ 173.1, 156.8,146.9, 143.2, 132.1, 130.9, 130.7, 130.5, 130.2, 126.3, 126.2, 124.7,118.5, 116.8, 100.1, 85.3, 79.5, 72.8, 69.5, 62.1, 41.7, 32.9, 29.2,23.6, 22.5; HRMS m/z: [M+Na⁺] for C₂₅H₃₀F₃NO₆Na, 520.1923; found,520.1934.

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2′-(methylthio)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11h)

Colorless amorphous solid (63% yield over 2 steps); ¹H NMR (400 MHz,CDCl3) δ 7.36 (t, 1H, J=7.0 Hz), 7.27 (m, 3H), 7.09 (m, 1H), 7.01 (m,1H), 6.87 (s, 1H), 5.64 (s, 1H), 5.54 (m, 1H), 4.16 (m, 2H), 3.32 (d,2H, J=8.8 Hz), 3.27 (m, 2H), 3.06 (s, 1H), 2.56 (t, 2H, J=6.2 Hz), 2.36(d, 3H, J=7.6 Hz), 1.83 (s, 3H), 1.33 (s, 3H), 1.20 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 170.3, 155.1, 155.0, 141.0, 138.9, 130.5, 130.1,129.8, 128.4, 124.6, 124.2, 118.3, 116.2, 115.9, 97.9, 84.5, 78.3, 71.5,68.7, 62.0, 53.6, 40.1, 31.7, 29.3, 23.3, 15.3, 15.2; HRMS m/z: [M+Na⁺]for C₂₅H₃₃NO₆SNa, calcd, 498.1926; found, 498.1925. This material wasdetermined to be 95% pure (retention time=7.465) by HPLC (PhenomenexLuna C-18, 5 μm, 10×250 mm column eluting with 30% CH₃CN, 70% H₂O, flowrate 5.0 mL/min).

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11i)

Colorless amorphous solid (41% yield over 2 steps); ¹H NMR (500 MHz,CDCl3) δ 7.36 (ddd, 1H, J=1.8, 7.6, 8.2 Hz), 7.18 (d, 1H, J=8.3 Hz),7.12 (t, 1H, J=5.8 Hz), 7.02 (m, 3H), 6.87 (dd, 1H, J=2.3, 11.3 Hz),5.54 (s, 1H), 5.39 (s, 1H), 4.21 (dt, 1H, J=3.3, 9.0 Hz), 4.15 (m, 1H),3.77 (d, 3H, J=6.9 Hz), 3.60 (s, 3H), 3.33 (d, 1H, J=8.7 Hz), 3.29 (m,2H), 2.73 (s, 1H), 2.66 (s, 1H), 2.60 (dd, 2H, J=6.5, 12.8 Hz), 1.84 (s,3H), 1.37 (s, 3H), 1.24 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.0,156.4, 155.2, 139.9, 131.2, 130.8, 130.2, 130.0, 129.2, 120.9, 118.6,118.3, 115.7, 115.2, 111.4, 111.2, 98.0, 97.9, 84.5, 78.2, 71.4, 68.7,62.0, 55.9, 55.9, 40.3, 31.9, 30.2, 29.3, 29.2, 23.4, 23.1; HRMS m/z:[M+H⁺] for C₂₅H₃₄NO₇, calcd, 460.2335; found, 460.2336. This materialwas determined to be 96.1% pure (retention time=5.057) by HPLC(Phenomenex Luna C-18, 5 μm, 10×250 mm column eluting with 30% CH₃CN,70% H₂O, flow rate 5.0 mL/min).

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-methoxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11j)

Colorless amorphous solid (53% yield over 2 steps); ¹H NMR (400 MHz,CDCl₃) δ 7.31 (t, J=7.9 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.02-6.96 (dd,J=8.5, 2.7 Hz, 1H), 6.92-6.83 (m, 4H), 6.81 (d, J=1.5 Hz, 2H), 5.54 (d,J=2.2 Hz, 1H), 5.45 (s, 1H), 4.25-4.16 (dd, J=9.1, 3.2 Hz, 1H),4.17-4.10 (dd, J=3.3, 2.2 Hz, 1H), 3.82 (s, 3H), 3.58 (s, 3H), 3.39-3.20(m, 3H), 3.24 (br s, OH), 2.97 (br s, OH), 2.75 (t, J=7.1 Hz, 2H), 1.85(s, 3H), 1.35 (s, 3H), 1.20 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.4,159.5, 155.3, 143.3, 142.8, 130.8, 129.5, 129.5, 121.7, 118.0, 115.3,115.1, 112.7, 98.1, 84.5, 78.4, 71.5, 68.7, 62.0, 55.4, 40.9, 32.0,29.1, 23.4, 23.1; HRMS m/z: [M+H⁺] for C₂₅H₃₄NO₇, calcd, 460.2335;found, 460.2322.

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-methyl-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11k)

Colorless amorphous solid (44% yield over 2 steps); ¹H NMR (400 MHz,CDCl₃) δ 7.32-7.27 (m, 1H), 7.16 (d, J=6.6 Hz, 2H), 7.10-7.04 (m, 2H),6.99 (d, J=8.5 Hz, 1H), 6.88 (s, 1H), 5.55 (s, 1H), 5.41 (s, 1H),4.25-4.08 (m, 2H), 3.57 (s, 3H), 3.37-3.20 (m, 5H), 2.75 (t, J=7.0 Hz,2H), 2.39 (s, 3H), 1.83 (s, 3H), 1.35 (s, 3H), 1.20 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 170.4, 155.3, 143.6, 141.3, 138.1, 130.8, 130.0,129.5, 128.3, 128.1, 126.3, 118.1, 115.1, 98.1, 84.5, 78.4, 71.5, 68.7,62.0, 40.9, 32.0, 29.2, 23.4, 23.1, 21.7; HRMS m/z: [M+H⁺] forC₂₅H₃₃NO₆Na, calcd, 466.2206; found, 466.2203.

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-(morpholinomethyl)-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11l)

Colorless amorphous solid (47% yield over 2 steps); ¹H NMR (500 MHz,CDCl₃) δ 7.41-7.29 (m, 2H), 7.27 (m, 1H), 7.19 (d, J=8.1 Hz, 2H),7.04-6.99 (dd, J=8.5, 2.7 Hz, 1H), 6.91 (d, J=2.7 Hz, 1H), 5.55 (d,J=2.4 Hz, 1H), 5.35 (s, 1H), 4.26-4.18 (dd, J=9.0, 3.3 Hz, 1H), 4.15 (t,J=2.8 Hz, 1H), 3.72 (t, J=4.7 Hz, 4H), 3.59 (s, 3H), 3.56 (s, 2H), 3.34(d, J=9.0 Hz, 1H), 3.30-3.21 (q, J=6.7 Hz, 2H), 2.75 (t, J=7.1 Hz, 2H),2.58-2.41 (m, 6H), 1.85 (s, 3H), 1.36 (s, 3H), 1.23 (s, 3H); ¹³C NMR(125 MHz, CDCl₃) δ 155.4, 143.4, 141.5, 137.8, 130.9, 130.1, 129.6,128.5, 128.3, 128.2, 118.2, 115.3, 98.1, 84.6, 78.4, 71.5, 68.8, 67.1,63.5, 62.0, 53.8, 40.7, 32.2, 29.2, 23.5, 23.2; HRMS (FAB) m/z: [M+Na⁺]for C₂₉H₄₀N₂O₇Na, calcd, 551.2728; found, 551.2734.

N-(2-(5-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-4′-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide(11m)

After cyclic carbonate hydrolysis following the same procedure ascompound 11a-p, the crude TBS protected compound was dissolved in THF (2mL) and tertrabutylammonium fluoride (1.5 eq.) was added dropwise at 0°C. under argon atmosphere. After 1 h the reaction was quenched withwater and extracted with EtOAc (3×10 mL); combined organic fractionswere washed with saturated aqueous sodium chloride, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography (SiO₂; 10:1, DCM:acetone) to afford acetamide 11m as aamorphous solid (40% yield over 3 steps). ¹H NMR (500 MHz, MeOD) δ 7.20(d, J=8.4 Hz, 1H), 7.15-7.08 (d, J=8.4 Hz, 2H), 6.96 (dd, J=8.4, 2.6 Hz,1H), 6.85-6.79 (m, 3H), 5.45 (d, J=2.4 Hz, 1H), 4.12 (dd, J=9.3, 3.3 Hz,1H), 3.96 (t, J=2.8 Hz, 1H), 3.59 (s, 3H), 3.21 (d, J=9.3, Hz, 1H), 3.16(dd, J=8.5, 6.5 Hz, 2H), 2.70 (dd, J=8.5, 6.5 Hz, 2H), 1.84 (s, 3H),1.32 (s, 3H), 1.18 (s, 3H); ¹³C NMR (125 MHz, MeOD) δ 173.1, 157.7,156.6, 144.7, 134.0, 131.7, 131.2, 131.1, 118.9, 116.0, 115.7, 100.1,85.4, 79.4, 72.8, 69.5, 62.1, 41.8, 33.0, 29.2, 23.6, 22.5; HRMS (FAB)m/z: [M+Na⁺] for C₂₄H₃₁NO₇Na, calcd, 468.1998; found, 468.1999.

N-(2-(benzo[d][1,3]dioxol-5-yl)-4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)phenethyl)acetamide(11n)

Colorless amorphous solid (51% yield over 2 steps); ¹H NMR (500 MHz,CDCl₃) δ 7.15 (d, J=8.5 Hz, 1H), 7.00-6.96 (dd, J=8.5, 2.7 Hz, 1H), 6.88(d, J=2.6 Hz, 1H), 6.84 (d, J=7.9 Hz, 1H), 6.76 (d, J=1.6 Hz, 1H),6.74-6.69 (m, 1H), 6.01 (s, 2H), 5.54 (d, J=2.4 Hz, 1H), 5.40 (s, 1H),4.21 (dd, J=9.1, 3.3 Hz, 1H), 4.14 (t, J=2.7 Hz, 2H), 3.58 (s, 3H), 3.33(d, J=9.1 Hz, 1H), 3.30-3.23 (q, J=6.9 Hz, 2H), 3.11 (br s, OH), 2.92(br s, OH), 2.74 (t, J=7.2 Hz, 2H), 1.86 (s, 3H), 1.34 (s, 3H), 1.20 (s,3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.2, 155.4, 147.7, 147.0, 143.1,135.3, 130.8, 129.7, 122.6, 118.3, 115.2, 109.9, 108.4, 101.3, 98.1,84.6, 78.4, 71.5, 68.8, 62.0, 40.8, 32.1, 29.2, 23.4, 23.2; HRMS (FAB)m/z: [M+Na⁺] for C₂₅H₃₁NO₈Na, calcd, 496.1947; found, 496.1940. Thismaterial was determined to be 98.4% pure (retention time=4.384) by HPLC(Phenomenex Luna C-18, 5 μm, 10×250 mm column eluting with 40% CH₃CN,60% H₂O, flow rate 5.0 mL/min).

N-(4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-(pyridin-3-yl)phenethyl)acetamide(11o)

Colorless amorphous solid (37% yield over 2 steps); ¹H NMR (500 MHz,CDCl₃) δ 8.55 (d, J=3.9 Hz, 1H), 8.49 (s, 1H), 7.60 (m, 1H), 7.35 (dd,J=7.8, 4.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.05-6.99 (dd, J=8.4, 2.7Hz, 1H), 6.85 (d, J=2.6 Hz, 1H), 5.52 (d, J=2.4 Hz, 1H), 5.36 (s, 1H),4.14 (dd, J=3.4, 9.1 Hz, 1H), 4.10 (t, J=2.7 Hz, 1H), 3.59 (s, 3H), 3.31(d, J=9.0 Hz, 1H), 3.27-3.20 (m, 2H), 2.68 (t, J=7.3 Hz, 2H), 1.86 (s,3H), 1.33 (s, 3H), 1.17 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.2,155.5, 149.8, 148.7, 139.5, 136.8, 131.1, 131.0, 130.6, 129.8, 123.4,118.3, 118.2, 116.1, 98.0, 84.5, 78.5, 71.4, 68.7, 62.1, 40.7, 32.2,29.2, 23.5, 23.1; HRMS (FAB) m/z: [M+Na⁺] for C₂₃H₃₁N₂O₆, calcd,431.2182; found, 431.2194.

N-(4-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-(pyridin-4-yl)phenethyl)acetamide(11p)

Colorless amorphous solid (42% yield over 2 steps); ¹H NMR (400 MHz,CDCl₃) δ 8.73-8.63 (dd, J=5.7, 3.9 Hz, 2H), 7.27-7.23 (m, 3H), 7.11-7.03(m, 1H), 6.86 (t, J=2.8 Hz, 1H), 5.55 (d, J=2.3 Hz, 1H), 5.41-5.31 (m,2H), 4.26-4.13 (m, 2H), 4.05 (d, J=6.9 Hz, 1H), 3.61 (s, 3H), 3.36-3.25(m, 2H), 2.78-2.71 (dd, J=8.3, 6.8 Hz, 2H), 1.90 (s, 3H), 1.39 (s, 3H),1.24 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.1, 155.5, 149.8, 140.5,131.4, 129.1, 124.4, 117.9, 116.3, 98.0, 94.1, 84.5, 71.5, 71.4, 68.7,62.1, 40.7, 32.2, 29.2, 28.8, 23.5, 23.1, 18.7; HRMS (FAB) m/z: [M+Na⁺]for C₂₃H₃₀N₂O₆Na, calcd, 453.2001; found, 453.1972.

Example 11. (Z)-4-(benzyloxy)-2-(methoxymethoxy)-1-(2-nitrovinyl)benzene(14)

Nitromethane (11.5 mL) was added to a mixture of aldehyde 13 (1.24 g,4.6 mmol) and ammonium acetate (0.63 g, 8.2 mmol) and heated to 50° C.Upon completion (20 min), the reaction mixture was cooled to RT andpurified without work-up by column chromatography (SiO₂, 4:1, Hex:EtOAc)to afford nitrostyrene 14 as a clear, colorless oil (1.22 g, 3.87 mmol,84%). ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J=13.4 Hz, 1H), 7.80 (d, J=13.6Hz, 1H), 7.50-7.32 (m, 6H), 6.88 (d, J=2.5 Hz, 1H), 6.67 (m, 1H), 5.30(s, 2H), 5.12 (s, 2H), 3.52 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.4,159.0, 136.1, 136.0, 135.6, 133.5, 128.8, 128.5, 127.7, 127.7, 113.0,108.6, 102.2, 94.7, 70.5, 56.6; HRMS (FAB) m/z: [M+Na⁺] for C₁₇H₁₇NO₅Na,calcd, 338.1004; found, 338.1007.

Example 12.4′-(benzyloxy)-2′-(methoxymethoxy)-2-nitro-1,2,3,6-tetrahydro-1,1′-biphenyl(15)

Nitrostyrene 14 (0.65 g, 2.06 mmol) was dissolved in toluene (0.6 mL) ina 2 mL sealed tube and cooled to −78° C. Butadiene was bubbled into thesolution to double the volume and then the tube was sealed and heated toreflux for 48 h. To prevent bumping of the butadiene gas, the tube wascooled again to −78° C. and used directly in purification by columnchromatography (SiO₂; 3:1, Hex:EtOAc) to afford cyclohexene 15 (0.72 g,1.96 mmol, 95%). ¹H NMR (500 MHz, CDCl₃) δ 7.40 (m, 4H), 7.36-7.28 (m,1H), 7.06 (d, J=8.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.56 (dd, J=8.4,2.5 Hz, 1H), 5.86-5.77 (m, 1H), 5.71 (ddd, J=9.8, 5.1, 2.3 Hz, 1H),5.27-5.20 (m, 1H), 5.20 (s, 2H), 5.00 (s, 2H), 3.70 (dt, J=17.0, 8.7 Hz,1H), 3.49 (s, J=12.7 Hz, 3H), 2.84-2.74 (m, 1H), 2.71 (ddd, J=13.2, 8.4,1.5 Hz, 1H), 2.45 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 159.2, 156.1,136.9, 129.3, 128.6, 127.0, 122.5, 120.9, 107.8, 120.6, 94.6, 85.6,70.1, 31.5, 31.3, 29.7.

Example 13.N-(4′-(benzyloxy)-2′-(methoxymethoxy)-1,2,3,6-tetrahydro-[1,1′-biphenyl]-2-yl)acetamide(16)

Nitro compound 13 (0.23 g, 0.62 mmol) was dissolved in isopropanol (12.4mL) and aqeous 1M HCl (6.2 mL). Zinc dust (811 mg, 12.4 mmol) was addedand the mixture was stirred vigorously for 1.5 h at 50° C. After coolingto room temperature, saturated NaHCO₃(8 mL) was added and the resultingmixture was stirred for an additional 20 min. The solids were removed byfiltration and the remaining solution was extracted with DCM (3×20 mL).The organic layers were combined and washed with saturated aqueoussodium chloride solution, dried (Na₂SO₄) and concentrated to affordamine as clear, colorless oil (0.20 g, 0.59 mmol, 95%).

Acetic anhydride (62 μL, 0.65 mmol) and triethylamine (95 μL, 0.68 mmol)were added to a solution of the amine (0.62 mmol) in DCM (6.2 mL) underan atmosphere at RT. After 3 h the reaction was quenched with saturatedaqueous ammonium chloride and extracted with DCM (3×10 mL); combinedorganic fractions were washed with Brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by column chromatography (SiO₂;3:1, Hex:EtOAc) to afford acetamide 16 (0.17 g, 0.46 mmol, 74%). ¹H NMR(500 MHz, CDCl₃) δ 7.42 (d, J=7.8 Hz, 2H), 7.39-7.33 (t, J=7.2 Hz, 2H),7.33-7.28 (m, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.77 (s, 1H), 6.63 (d, J=8.5Hz, 1H), 5.90 (d, J=8.4 Hz, 1H), 5.71 (d, J=36.2 Hz, 2H), 5.17 (s, 2H),5.02 (s, 2H), 4.36-4.23 (dtd, J=13.8, 10.4, 9.9, 7.2 Hz, 1H), 3.50 (s,3H), 3.31-3.22 (dd, J=18.6, 7.9 Hz, 1H), 2.59 (d, J=17.3 Hz, 1H), 2.33(s, 2H), 2.02-1.93 (m, 1H), 1.74 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ169.8, 158.3, 156.1, 136.9, 128.5, 128.3, 127.9, 127.6, 126.7, 125.0,124.4, 108.0, 102.9, 95.6, 70.0, 56.2, 48.8, 37.4, 33.0, 32.6, 23.1;HRMS (FAB) m/z: [M+Na⁺] for C₂₃H₂₇NO₄Na, calcd, 404.1832; found,404.1827.

Example 14.N-(4′-(benzyloxy)-2′-hydroxy-1,2,3,6-tetrahydro-[1,1′-biphenyl]-2-yl)acetamide

Catalytic amount of conc. HCl (few drops) was added to MOM protectedphenol 16 (0.27 g, 0.71 mmol) in methanol (7.1 mL) and stirredvigorously at 50° C. for overnight. Upon completion the reaction mixturewas concentrated and was purified by column chromatography (SiO₂; 5:100,MeOH:DCM) to afford phenol (0.19 g, 0.58 mmol, 81%). ¹H NMR (400 MHz,CDCl₃) δ 8.86 (s, 1H), 7.41-7.25 (m, 5H), 7.01 (d, J=8.5 Hz, 1H), 6.73(d, J=2.4 Hz, 1H), 6.48 (d, J=6.0 Hz, 1H), 5.73 (m, 1H), 5.65 (m, 1H),4.96 (s, 2H), 4.26 (m, 1H), 3.42 (m, 1H), 2.55-2.12 (m, 4H), 1.98 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.2, 158.3, 155.4, 136.9, 128.5,128.0, 127.9, 127.6, 127.0, 123.9, 121.1, 107.2, 103.4, 69.9, 51.9,50.0, 36.6, 31.6, 21.0; HRMS (FAB) m/z: [M+Na⁺] for C₂₁H₂₃NO₃Na, calcd,360.1576; found, 360.1571.

Example 15.2′-acetamido-4-(benzyloxy)-1′,2′,3′,6′-tetrahydro-[1,1′-biphenyl]-2-yltrifluoromethanesulfonate (17)

A solution of phenol (0.19 g, 0.58 mmol) in anhydrous DCM (5.8 mL) wasstirred at 0° C. and triethylamine (0.12 mL, 0.87 mmol) was addedfollowed by N-phenyl-bis(trifluoromethanesulfonimide) (0.31 g, 0.87mmol). Upon completion the reaction was quenched by addition of water(50 mL), washed with saturated aqueous NaCl solution, dried (Na₂SO₄),filtered and concentrated. The residue was purified by columnchromatography (SiO₂, 3:1, Hex:EtOAc) to afford triflate 17 as a clear,yellow oil (0.23 g, 0.49 mmol, 85%). ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.31(m, 6H), 7.00 (d, J=11.2 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 5.70 (m, 2H),5.60 (d, J=9.3 Hz, 1H), 5.04 (s, 2H), 4.53-4.38 (dt, J=15.2, 10.2 Hz,1H), 3.18-3.03 (td, J=11.2, 5.2 Hz, 1H), 2.63-2.50 (dd, J=16.2, 4.2 Hz,1H), 2.42-2.32 (m, 1H), 2.28-2.15 (m, 1H), 2.11-1.97 (t, J=14.5 Hz, 1H),1.71 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.7, 158.2, 147.6, 136.0,129.9, 128.8, 128.5, 128.1, 127.7, 126.1, 125.4, 115.8, 108.2, 70.7,48.3, 38.5, 34.8, 33.7, 23.2; HRMS (FAB) m/z: [M+Na⁺] forC₂₂H₂₂F₃NO₅SNa, calcd, 492.106318; found, 492.1067.

Example 16.N-(4′-(benzyloxy)-3″-fluoro-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide(18a)

Followed same Suzuki coupling procedure as described above for 6a-p. ¹HNMR (400 MHz, CDCl₃) δ 7.47-7.30 (m, 7H), 7.13-7.05 (t, J=8.9 Hz, 1H),7.05-7.00 (t, J=7.2 Hz, 2H), 6.97 (d, J=10.9 Hz, 1H), 6.80 (d, J=2.7 Hz,1H), 5.72-5.53 (m, 2H), 5.06 (s, 2H), 4.91 (d, J=8.7 Hz, 1H), 4.36-4.24(m, 1H), 2.90-2.75 (dd, J=19.2, 8.2 Hz, 1H), 2.59-2.45 (dt, J=16.3, 4.4Hz, 1H), 2.36 (m, 2H), 1.75 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.3,156.8, 143.9, 142.3, 137.0, 132.6, 130.2, 130.2, 128.8, 128.5, 128.2,127.8, 126.7, 125.2, 125.0, 116.4, 116.2, 116.0, 115.2, 114.5, 114.3,70.2, 49.4, 40.5, 35.3, 33.4, 23.5; HRMS (FAB) m/z: [M+Na⁺] forC₂₇H₂₆FNO₂Na, calcd, 438.1840; found, 438.1818.

N-(4′-(benzyloxy)-3″-(trifluoromethyl)-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide(18b)

Followed same Suzuki coupling procedure as described above for 6a-p. ¹HNMR (400 MHz, CDCl₃) δ 7.73-7.30 (m, 10H), 7.05 (d, J=8.7 Hz, 1H), 6.85(s, 1H), 5.66 (m, 2H), 5.16 (d, J=8.5 Hz, 1H), 5.08 (s, 2H), 4.43-4.29(m, 1H), 2.90-2.74 (q, J=10.0, 9.0 Hz, 1H), 2.50 (d, J=17.7 Hz, 1H),2.40-2.28 (dd, J=6.9, 3.9 Hz, 2H), 1.75 (s, 3H); ¹³C NMR (101 MHz,CDCl₃) δ 169.7, 156.9, 142.4, 141.9, 136.9, 132.6, 131.1, 130.8, 129.1,128.7, 128.6, 128.2, 127.7, 126.6, 126.0, 125.9, 125.0, 124.3, 124.2,116.3, 115.3, 70.2, 49.4, 40.6, 35.2, 33.1, 23.4; HRMS (FAB) m/z:[M+Na⁺] for C₂₈H₂₆F₃NO₂Na, calcd, 488.1813; found, 488.1812.

Example 17.N-(3″-fluoro-4′-hydroxy-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide(19a)

1,2-Ethanedithiol (0.22 mL, 2.66 mmol) and BF₃OEt₂ (0.176 mL, 1.4 mmol)were added to benzyl ether 18a (64 mg, 0.14 mmol) in DCM (1.8 mL). After8 h, reaction mixture was concentrated and purified by columnchromatography (SiO₂, 10:100, MeOH:DCM) to afford phenol 19a as anamorphous solid (45 mg, 0.12 mmol, 86%)¹H NMR (500 MHz, CDCl₃) δ 8.98(s, 1H), 7.40-7.34 (q, J=7.1, 6.2 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H),7.10-7.01 (m, 2H), 6.96 (d, J=9.4 Hz, 1H), 6.84-6.79 (dd, J=8.5, 2.6 Hz,1H), 6.68 (d, J=2.6 Hz, 1H), 5.73-5.52 (m, 2H), 4.51-4.38 (dt, J=9.9,5.0 Hz, 1H), 2.88-2.77 (q, J=9.5, 7.9 Hz, 1H), 2.43 (d, J=17.3 Hz, 1H),2.34 (m, 2H), 2.18 (s, 1H), 1.77 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ170.5, 163.6-161.7 (d, J=244.0 Hz), 155.2, 144.2 (d, J=7.6 Hz), 142.3,130.8, 130.1 (d, J=8.4 Hz), 128.2, 127.0, 125.0 (d, J=2.2 Hz), 124.7,116.5, 116.3 (d, J=20.3 Hz), 115.9, 114.2 (d, J=20.3 Hz, 49.6, 40.8,35.5, 33.5, 23.2; HRMS (FAB) m/z: [M+Na⁺] for C₂₁H₂₅FNO₂Na, 348.1376;found, 348.1379.

N-(4′-hydroxy-3″-(trifluoromethyl)-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide(19b)

Followed same procedure as for 19a. ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s,1H), 7.66-7.56 (m, 4H), 7.29 (d, J=8.5 Hz, 1H), 6.82-6.72 (d, J=10.5 Hz,1H), 6.65 (s, 1H), 5.65 (m, 1H), 5.54 (m, 1H), 5.21 (d, J=9.7 Hz, 2H),4.56-4.33 (m, 1H), 2.76-2.61 (m, 1H), 2.46-2.24 (m, 3H), 1.75 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 170.5, 155.3, 142.7, 142.0, 132.6, 130.8, 130(q, J=32.5 Hz), 128.8, 128.4, 126.9, 126.0 (m), 124.7, 124.0 (m), 116.7,116.0, 49.6, 40.9, 35.6, 33.5, 23.2; HRMS (FAB) m/z: [M+Na⁺] forC₂₁H₂₀F₃NO₂Na, calcd, 398.1344; found, 398.1346.

Example 18.N-(4′-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3′-fluoro-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide(20a)

Followed same noviose coupling procedure as described above for 11a-p toafford 20a as a inseparable mixture of diastereomers. ¹H NMR (500 MHz,CDCl3) δ 7.32 (ddd, 1H, J=6.0, 7.9, 13.9 Hz), 7.22 (dd, 1H, J=2.8, 8.7Hz), 7.00 (m, 2H), 6.94 (d, 1H, J=7.6 Hz), 6.87 (m, 1H), 6.77 (dd, 1H,J=2.7, 8.7 Hz), 5.59 (m, 1H), 5.52 (m, 1H), 5.49 (d, 1/2H, J=2.4 Hz),5.45 (d, 1/2H, J=2.4 Hz), 4.81 (dd, 1H, J=2.5, 8.8 Hz), 4.21 (m, 1H),4.12 (m, 1H), 4.07 (m, 1H), 3.52 (s, 3H), 3.25 (dd, 1H, J=0.9, 9.0 Hz),2.89 (br s, 1H), 2.76 (m, 1H), 2.67 (s, 1H), 2.26 (m, 2H), 1.69 (m, 1H),1.65 (s, 3/2H), 1.64 (s, 3/2H), 1.29 (s, 3/2H), 1.28 (s, 3/2H), 1.13 (s,3/2H), 1.12 (s, 3/2H); ¹³C NMR (125 MHz, CDCl₃) δ 169.4, 169.4,163.7-161.7 (d, J=249.0 Hz), 154.9, 154.7, 143.0 (dd, J=1.7, 8.5 Hz),142.2 (d, J=1.7 Hz), 133.4, 133.3, 130.2 (dd, J=1.7, 8.5 Hz), 128.4 (d,J=5.0 Hz), 126.6 (d, J=3.2 Hz), 125.1 (d, J=3.6 Hz), 125.0 (m), 117.2,116.9, 116.6, 116.3 (dd, J=13.4, 20.9 Hz), 116.2, 114.3 (dd, J=1.5, 20.9Hz), 98.0, 97.7, 84.5, 84.4, 78.3, 78.3, 77.4, 71.5, 71.4, 68.8, 62.0,61.9, 49.6, 49.6, 40.5, 40.5, 35.2, 35.1, 33.4, 29.2, 23.6, 23.5, 23.2,23.1; HRMS (FAB) m/z: [M+Na⁺] for C₂₈H₃₄FNO₆Na, 522.2262; found,522.2267.

N-(4′-(((3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3″-(trifluoromethyl)-1,2,3,6-tetrahydro-[1,1′:2′,1″-terphenyl]-2-yl)acetamide(20b)

Followed same noviose coupling procedure as described above for 11a-p toafford 20b as a inseparable mixture of diastereomers. ¹H NMR (500 MHz,CDCl₃) δ 7.65 (d, 1H, J=8.2 Hz), 7.56 (t, 1H, J=7.7 Hz), 7.49 (s, 1H),7.45 (d, 1H, J=7.6 Hz), 7.32 (dd, 1H, J=3.0, 8.7 Hz), 7.08 (td, 1H,J=2.7, 8.6 Hz), 6.85 (dd, 1H, J=2.7, 8.5 Hz), 5.65 (m, 1H), 5.59 (m,1H), 5.57 (d, 1/2H, J=2.4 Hz), 5.53 (d, 1/2H, J=2.3 Hz), 4.90 (t, 1H,J=8.2 Hz), 4.30 (m, 1H), 4.19 (dd, 1H, J=4.3, 8.2 Hz), 4.14 (m, 1H),3.59 (s, 3/2H), 3.59 (s, 3/2H), 3.33 (d, 1H, J=9.0 Hz), 3.17 (s, 1H),2.95 (s, 1H), 2.76 (m, 1H), 2.49 (m, 1H), 2.33 (m, 1H), 1.74 (m, 1H),1.73 (s, 3/2H), 1.72 (s, 3/2H), 1.36 (s, 3/2H), 1.35 (s, 3/2H), 1.21 (s,3/2H), 1.20 (s, 3/2H); ¹³C NMR (100 MHz, CDCl₃) δ 169.4, 169.4, 155.0,154.8, 142.3, 141.8, 133.4, 133.3, 132.8, 132.6, 131.8 (dq, J=2.2, 32.5Hz), 129.1, 128.6, 126.5, 125.9 (q, J=3.2, 7.0 Hz), 125.0, 124.2, 117.6,117.0, 116.8, 98.1, 97.8, 84.5, 84.4, 78.4, 78.3, 71.3, 71.3, 68.7,68.7, 61.9, 61.9, 49.4, 49.3, 40.5, 40.5, 35.1, 35.0, 33.1, 29.0, 29.0,23.4, 23.4, 23.1, 23.0; HRMS (FAB) m/z: [M+Na⁺] for C₂₉H₃₄F₃NO₆Na,Calcd, 572.2230; found, 572.2227.

Example 19. Synthesis of Carbocyclic AnalogueN-(2-(5-((4-(benzyloxy)cyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(24) 4-hydroxycyclohexyl 4-methylbenzenesulfonate (21)

To a solution of pyridine (4 g, 0.025 mol) in CHCl₃ (25 mL) was addedCyclohexanediol (2.5 g, 0.021 mol) at room temperature. This was thencooled to 0° C., and tosyl chloride (4.1 g, 0.021) added to the mixture.The reaction was stirred for 16 h under argon at room temperature. Uponcompletion of the reaction from TLC, the reaction mixture was pouredinto dilute HCl, and the solid precipitate collected by filtration,washed with water and dried (Na₂SO₄).

4-(benzyloxy)cyclohexyl 4-methylbenzenesulfonate (22)

To a solution of 21 (0.5 mg, 1.8 mmol) in acetonitrile (3 mL) was addedsodium hydride (0.11 g, 2.7 mmol) at 0° C. A solution of benzyl bromide(0.48 mL, 2 mmol) in acetonitrile (2 mL) was then added to the mixturedropwise, under an argon atmosphere. The reaction was stirred for 16 hat room temperature. Upon completion, distilled water (10 mL) was addedto the mixture and the organic layer extracted into ethyl acetate. Theorganic layers were combined, dried and concentrated to give a crudemixture that was purified by column chromatography (Silica gel, 10%-20%EtOAc in hexane) to give 22(300 mg) as a white solid.

N-(2-(5-((4-(benzyloxy)cyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(24)

To a solution of phenol 23 (45 mg, 0.16 mmol) in DMF (1 mL) was addedpotassium carbonate (30 mg, 0.19 mmol) and stirred at room temperaturefor 30 min, after which 22 (75 mg, 0.19 mmol) and TBAI (7 mg, 0.016mmol) were added to the solution, and heated to reflux overnight. Uponcompletion, distilled water (5 mL) was added to the mixture and theorganic layer extracted into ethyl acetate. After removal of the solventon a rotor evaporator, the crude mixture was purified by columnchromatography (Silica gel, 40% EtOAc in hexane) to give 24 (8 mg) as awhite solid.

Synthesis of phenol core intermediate 23.

4-(benzyloxy)-2-hydroxybenzaldehyde (25)

2,4-dihydroxybenzaldehyde (10 g, 0.072 mol) was dissolved inacetonitrile (83 mL). To this solution was added NaHCO₃ (9.1 g, 0.10mol) and stirred for 5 min. Benzyl bromide (12.9 mL, 0.10 mol) was addedin under an argon atmosphere. The reaction was heated to reflux for 16h. After cooling to room temperature, the reaction was quenched byaddition of distilled water, and the organic layer extracted intodichloromethane (3×50 mL), and organic layers combined, washed withwater and brine, dried (Na₂SO₄) and concentrated. The crude mixture waspurified by column chromatography (Silica gel, 10%-20% EtOAc in hexane)to give 25 in 65% yield.

5-(benzyloxy)-2-formylphenyl trifluoromethanesulfonate (26)

A solution of 25 (1.1 g, 4.9 mmol) in freshly distilled dichloromethane(10 mL) was stirred at 0° C. Triethylamine (1.02 mL, 7.35 mmol) wasadded to this solution followed by triflic anhydride (1.38 mL, 6.35mmol) over 5 min. Upon completion of the reaction from TLC, the reactionwas quenched by addition of distilled water and extracted intodichloromethane (3×10 mL). The organic layers were combined and dried(Na₂SO₄). After removal of the solvent on a rotor evaporator, the crudebrown mixture was purified by column chromatography (Silica gel, 10%EtOAc in hexane) to give 26 in 55% yield.

5-(benzyloxy)-3′-fluoro-[1,1′-biphenyl]-2-carbaldehyde (27)

A solution of 26 (246 mg, 0.68 mmol), boronic acid (92 mg, 0.75 mmol),Pd(PPh₃)₄ (70.4 mg, 0.068 mmol) and K₂CO₃ (0.169 g, 1.2 mmol) inanhydrous DMF (7 mL) in a sealed tube, was degassed with argon for 10minutes at room temperature. After this, the reaction mixture was heatedto reflux for 16 h. Upon completion of the reaction from TLC, thereaction was cooled to room temperature and quenched by addition ofsaturated NaHCO₃ and extracted into ethyl acetate (3×5 mL). The organiclayers were combined and washed with brine, dried (Na₂SO₄), andconcentrated. The crude brown mixture was purified by columnchromatography (Silica gel, 20% EtOAc in hexane) to give the desiredproduct.

(E)-5-(benzyloxy)-3′-fluoro-2-(2-nitrovinyl)-1,1′-biphenyl (28)

0.37 g, 1.2 mmol of 7 was added to a flask containing 3.3 mLnitromethane. Ammonium acetate (1.8 g, 2.2 mmol) was added to thesolution and the resulting mixture stirred at 50° C. until the reactionwas complete as evidenced by the disappearance of starting material onTLC. The reaction mixture was then cooled to room temperature andpurified by silica gel column chromatography using 3:1 hexane:EtOAcmixture as eluent, giving the desired product in 93% yield.

2-(5-(benzyloxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethanamine (29)

Nitrostyrene 28 (400 mg, 1.1 mmol) in freshly distilled THF (2 mL) wasadded dropwise to a solution of LiAlH₄ (87 mg, 2.2 mmol), at 0° C. underan argon atmosphere. Upon completion of the reaction (from TLC) thereaction was quenched by addition of water (45 μL), 3M NaOH (45 μL), andan additional 80 μL water, and 20 mL EtOAc. The resulting mixture wasstirred at room temperature for 1 h, filtered through a plug of celite,washed with EtOAc, dried (Na₂SO₄) and concentrated to a crude brownmixture, which was purified by column chromatography (Silica gel, 10%MeOH in DCM) to give the desired product.

N-(2-(5-(benzyloxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (30)

80 mg, 0.25 mmol of 29 was added to a 25 mL oven-dried flask containing5 mL freshly distilled DCM, under argon atmosphere. Acetic anhydride (21μL, 0.22 mmol) and triethyl amine (35 μL) were then added to thesolution and the resultant mixture stirred at room temperature for 3 h.The reaction mixture was then quenched by addition of saturated ammoniumchloride, and extracted into DCM. The combined organic layers were dried(Na₂SO₄) and concentrated to a crude mixture, which was purified bycolumn chromatography (Silica gel, 3:1 hexane:EtOAc) to give the desiredproduct.

N-(2-(3′-fluoro-5-hydroxy-[1,1′-biphenyl]-2-yl)ethyl)acetamide (23)

400 mg of 10 was added to a 10 mL round bottom flask containingmethanol, and 10 mol % Pd(OH)₂ was added to the flask. This wassubjected to degassing using a hydrogen balloon attached, for 10 min,and then left stirring at room temperature under a hydrogen atmospherefor 8 h. The reaction was filtered, and concentrated to give pureproduct 23 that was used without further purification.

Example 20. Synthesis of Carbocyclic AnaloguesN-(2-(5-((4-(benzyloxy)cyclohex-2-en-1-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2yl)ethyl)acetamide(36), andN-(2-(5-((4-(benzyloxy)-2,3-dihydroxycyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(37) 1,2-di(oxiran-2-yl)ethane (32)

To a solution of 1,5-hexadiene (5 g, 0.12 mol) in freshly distilled DCM(100 mL) at 0° C. was added mCPBA. (12.5 g, 0.146 mol, 70% by wt.) Thesuspension was stirred at room temperature for 2 h. The reaction waswashed with saturated NaHCO₃ solution, (4×80 mL) followed by brine. (100mL) The organic layers were then dried (Na₂SO₄) and concentrated. Theresidue was purified by flash column chromatography using 5-20%EtOAc/hex as eluent, to give the desired product in 65% yield.

1,6-Heptadiene-3,5-diol (33)

To a stirred solution of tri-methylsulfonium iodide (6.12 g, 30 mmol) indry THF (50 mL) at −10° C. was added drop-wise butyllithium (14 mL, 2.5M in hexane). The reaction mixture was stirred at −10° C. for 30 min,and a solution of diepoxide 32 (570 mg, 5 mmol) in dry THF (5 mL) wasadded. The reaction mixture was allowed to warm to room temperature, andthe white suspension was stirred overnight. The mixture was treated witha saturated aqueous NH₄Cl solution (15 mL), extracted with CH₂Cl₂ (3×10mL), dried over Na₂SO₄, and concentrated. The crude product was purifiedon silica gel (pentane/ether 50/50) to yield the compound 33 (360 mg,45% yield)

cyclohex-2-ene-1,4-diol (34)

To a stirred solution of 33 (190 mg, 1.3 mmol) in DCM (0.1M) was addedGrubbs Catalyst, 2nd Generation. (22 mg, 0.026 mmol) The reactionmixture was heated to reflux for 2 h and was then concentrated undervacuum. The crude product was purified by column chromatography onsilica gel with 50-100% EtOAc/hex to yield the desired compound.

4-(benzyloxy)cyclohex-2-en-1-ol (35)

To a solution of 34 (79 mg, 0.69 mmol) in DMF (1 mL) was added sodiumhydride (14 mg, 0.62 mmol) at 0° C. Benzyl bromide (73 μL, 0.62 mmol)was added to the mixture dropwise, under an argon atmosphere. Thereaction was stirred for 16 h at room temperature. Upon completion,distilled water (3 mL) was added to the mixture and the organic layerextracted into ethyl acetate. The organic layers were combined, driedand concentrated to give a crude mixture that was purified by columnchromatography (Silica gel, 10%-20% EtOAc in hexane) to give 35 as anoil.

N-(2-(5-((4-(benzyloxy)cyclohex-2-en-1-yl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide(36)

To a solution of 35 (70 mg, 0.34 mmol) in freshly distilled THF (3 mL)at 0° C. was added triphenyl phosphine (180 mg, 0.68 mmol) and 23 (90mg, 0.34 mmol). DIAD (0.135 mL, 0.68 mmol) was added to the mixturedropwise. The reaction was warmed to room temperature and stirred for 4h. The reaction mixture was treated with saturated aqueous NaHCO₃solution (2 mL), washed with water, followed by brine, dried overNa₂SO₄, and concentrated to give a crude mixture that was purified bycolumn chromatography (30% 50% EtOAc in hexane) to give 36 as an oil.

N-(2-(5-((4-(benzyloxy)-2,3-dihydroxycyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2yl)ethyl)acetamide(37)

To a solution of 36 (15 mg, 0.032 mmol) in a mixture of THF/H₂O, (1:1, 1mL) was added catalytic amount of OsO₄ (0.0032 mmol) and NMO. (5.7 mg,0.048 mmol) The resulting solution was stirred at room temperatureovernight. THF was evaporated and the residue extracted with EtOAc. Theorganic layer was washed with saturated NaHCO₃ followed by saturatedNH₄Cl, dried, (Na₂SO₄) concentrated and purified (50%-100% EtOAc inhexane) to give 37.

Example 21. Synthesis of Carbocyclic AnalogueN-(2-(5-((4-(tert-butyl)cyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (39) 4-(tert-butyl)cyclohexyl 4-methylbenzenesulfonate (38)

4-(tert-butyl)cyclohexan-1-ol (500 mg, 3 mmol) was dissolved in pyridine(50 mL) and stirred at room temperature for 30 min. Tosyl chloride (915mg, 4.79 mmol) was added to the reaction mixture and allowed to stirovernight. The reaction was quenched by addition of water (50 mL) andextracted with ether. (3×20 mL) washed with saturated CuSO₄, water,saturated aqueous NaHCO₃, water, and dried, (Na₂SO₄) concentrated andpurified (10% EtOAc in hexane) to give 38 as a white solid.

N-(2-(5-((4-(tert-butyl)cyclohexyl)oxy)-3′-fluoro-[1,1′-biphenyl]-2-yl)ethyl)acetamide (39)

To a solution of 38 (50 mg, 0.16 mmol) in anhydrous DMF (2 mL) was addedK₂CO₃, (24 mg) 38 (44 mg, 0.16 mmol) and TBAI (6 mg). The solutionmixture was heated to 80° C. for 4 days. Upon completion, distilledwater (4 mL) was added to the mixture and the organic layer extractedinto ethyl acetate. After removal of the solvent on a rotor evaporator,the crude mixture was purified by column chromatography (50% EtOAc inhexane) to give 39.

From the foregoing it will be seen that this invention is one welladapted to attain all ends and objectives herein-above set forth,together with the other advantages which are obvious and which areinherent to the invention. Since many possible embodiments may be madeof the invention without departing from the scope thereof, it is to beunderstood that all matters herein set forth or shown in theaccompanying drawings are to be interpreted as illustrative, and not ina limiting sense. While specific embodiments have been shown anddiscussed, various modifications may of course be made, and theinvention is not limited to the specific forms or arrangement of partsand steps described herein, except insofar as such limitations areincluded in the following claims. Further, it will be understood thatcertain features and subcombinations are of utility and may be employedwithout reference to other features and subcombinations. This iscontemplated by and is within the scope of the claims.

1.-18. (canceled)
 19. A method of preparing a compound of the formula:

wherein R₁ is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl,alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido,amino, alkoxy, sulfanyl, sulfenyl, sulfonyl, or ether; R₂ is hydrogen,halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl, alkynyl,carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic, or—R₉—OR₁₀, wherein R₉ is a covalent bond or alkyl, and R₁₀ is hydrogen,alkyl, C-amido or acyl; or R₂ together with R₃ and the atoms to whichthey are attached form a carbocyclic ring with 5 to 7 ring members or aheterocyclic ring having 4 to 8 ring members with at least oneheteroatom selected from oxygen or nitrogen; R₃ is hydrogen, hydroxy,halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl, or —R₁₁—O—R₁₂, whereinR₁₁ is a covalent bond or alkyl, and R₁₂ is alkyl, C-amido, or acyl; orR₃ together with R₂ and the atoms to which they are attached form acarbocyclic ring with 5 to 7 ring members or a heterocyclic ring having4 to 8 ring members with at least one heteroatom selected from oxygen ornitrogen; R₄ is hydrogen or alkyl; R₅ is hydrogen or alkyl; R₆ ishydrogen, hydroxy, sulfanyl, alkyl, or alkoxy; R₇ is hydrogen orhydroxyl; R₈ is hydrogen or hydroxyl; X is ═CR₂₁— or ═N—, wherein R₂₁ ishydrogen, halo, trifluoromethyl, alkyl, alkenyl, alkynyl, alkoxy, orhydroxy; R′ is hydrogen or alkyl; R″ is alkyl; Y is ═CR₃— or ═N—; Z isCH or Z—Z₁ is —C═C—; Z₁ is CH or Z—Z₁ is —C═C—; and n is 0, 1, 2, or 3.comprising reacting an aglycone of the formula:

wherein: R₁ is hydrogen, hydroxy, halo, trifluoroalkyl, alkyl, alkenyl,alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido,amino, alkoxy, sulfanyl, sulfenyl, sulfonyl, or ether; R₂ is hydrogen,halo, hydroxy, trifluoromethyl, alkoxy, alkyl, alkenyl, alkynyl,carbocyclic, alkylcarbocyclic, alkylheterocyclic, heterocyclic, or—R⁹—OR¹⁰, wherein: R⁹ is a covalent bond or alkylene, and R¹⁰ ishydrogen, alkyl, C-amido, or acyl; or R₂ together with R₃ and the atomsto which they are attached form a carbocyclic ring with 5 to 7 ringmembers or a heterocyclic ring having 4 to 8 ring members with at leastone heteroatom selected from oxygen or nitrogen; R₃ is hydrogen,hydroxy, halo, trifluoroalkyl, alkyl, alkoxy, sulfanyl, or —R¹¹—O—R¹²,wherein: R¹¹ is a covalent bond or alkylene, and R¹² is alkyl, C-amido,or acyl; or R₃ together with R₂ and the atoms to which they are attachedform a carbocyclic ring with 5 to 7 ring members or a heterocyclic ringhaving 4 to 8 ring members with at least one heteroatom selected fromoxygen or nitrogen; or R₃ is absent when Y is ═N—; R′ is H or alkyl; R″is alkyl, alkoxy, haloalkyl, alkylcycloalkyl, or alkylamidoalkyl; X is═CR²¹— or ═N—, wherein: R²¹ is hydrogen, halo, trifluoromethyl, alkyl,alkenyl, alkynyl, alkoxy, or hydroxy; and Y is ═CR₃— or ═N—; with asugar of the formula:

wherein: R₄ is hydrogen or alkyl; R₅ is hydrogen or alkyl; R₆ ishydrogen, hydroxy, sulfanyl, alkyl, or alkoxy; R₇ is hydrogen orhydroxyl; R₈ is hydrogen or hydroxyl; Z is CH or Z—Z₁ is —C═C—; Z₁ is CHor Z—Z₁ is —C═C—; and n is 0, 1, 2, or
 3. in the presence of a Lewisacid.
 20. The method of claim 19, wherein R₂ is halo.
 21. The method ofclaim 20, wherein R₂ is fluoro.
 22. The method of claim 19, wherein R₁is hydrogen.
 23. The method of claim 19, wherein R₃ is hydrogen.
 24. Themethod of claim 19, wherein X is ═CR²¹—, wherein R²¹ is hydrogen. 25.The method of claim 19, wherein Y is ═CR³—.
 26. The method of claim 19,wherein R′ is hydrogen.
 27. The method of claim 19, wherein R″ is alkyl.28. The method of claim 19, wherein R₄ and R₅ are alkyl.
 29. The methodof claim 19, wherein R₆ is alkoxy.
 30. The method of claim 19, whereinR₇ and R₈ are hydroxy.
 31. The method of claim 19, wherein the aglyconeis:


32. The method of claim 19, wherein the sugar is:


33. The method of claim 19, wherein the compound is:


34. The method of claim 19, wherein the Lewis acid is a boron compound.35. The method of claim 34, wherein the boron compound is BF₃.
 36. Themethod of claim 19 further comprising adding a base.
 37. The method ofclaim 36, wherein the base is triethylamine.
 38. The method of claim 19further comprising an alcohol.